Hypothalamic Activation in Spontaneous Migraine Attacks

Marie Denuelle, MD; Nelly Fabre, MD; Pierre Payoux, MD; Francois Chollet, MD; Gilles Geraud, MD


Headache. 2007;47(10):1418-1426. 

In This Article


Our study confirms the role of midbrain and pontine nuclei in migraine attacks. Furthermore, hypothalamic activation during spontaneous attacks of migraine without aura is shown for the first time. A flaw in the design of this study relates to the timing of the scans. Ideally, the order of the spontaneous attack and the attack-free scans would have been randomized. For organizational reasons, we could not do this.

Until now, to our knowledge, only 2 studies have recorded spontaneous attacks of migraine withPET.[1,2] Our results confirm and elaborate upon the observations of these researchers. We found activation of brainstem nuclei, and of cortical areas involved in pain processing such as the cingulate, insular, and prefrontal cortices. These cortical structures could both respond to pain and participate in pain control,[8] which could explain the persistence of cortical activations after headache relief. Although the precise participation of these areas in patients' relief remains unknown, their functional role in animals and humans suggests that they might either contribute to normalize stress, anticipatory and mood processes, or activate descending inhibitory controls of pain. Other studies that provoked migraine attacks also observed brainstem activation.[3,4] However, the sites of activation within the brainstem have varied between the datasets. Activation has been described in the midbrain that could correspond to the dorsal raphe nucleus, periaqueductal gray, and locus coeruleus,[1] red nucleus, substantia nigra,[4] and the dorsolateral pons.[2,3] The brainstem activation that we observed includes all the above regions in the midbrain and pons.

Significantly, none of previous studies observed the hypothalamic activation seen in the current study. There are several facts that may account for this discrepancy. Afridi etal[2] scanned their subjects up to 24 hours post headache onset, a much longer delay than the 4 hour maximum in our study. Weiller etal.'s study[1] was carried out 10 years ago; advances in PET camera technology and analysis methods have been made since 1995. First, thePETsystem used in our study is an EXACT-HR+ with an improvement of spatial resolution (4.5×4.1mm).[9] Second, we replicated each condition of activation leading to an increase of statistical significance of ancova analysis. Lastly,we used a recent version of SPM (SPM2), which improves the quality of spatial normalization in order to compare patients. With regard to the provoked attacks studies, the question of the similarity with spontaneous attacks can be raised. The premonitory symptoms reported in GTN-induced migraine were thought to be an argument in favor of an identical neurological process in spontaneous migraine attacks and GTN-induced migraine.[10] But the premonitory symptoms suggesting a hypothalamic dysfunction such as hunger, thirst, frequency of urination, and low mood described in spontaneous attacks are not reproducible during a GTN-induced migraine.[10]

The existence of a hypothalamic activation is here demonstrated for the first time in migraine without aura. So far a hypothalamic activation was only demonstrated in cluster headache[11] and related disorders with autonomic involvement such as trigemino-autonomic-cephalgias (TAC) in the absence of brainstem activation.[12] These data led to the conception that the pathophysiology of migraine and cluster headaches/TACs were clearly distinct.[13,14] Our results do not support this distinction. Other recent reports also suggest that the distinction is unwarranted: coactivation of the hypothalamus and brainstem has been reported in hemicrania continua,[15] paroxysmal hemicrania,[16] and in a case of spontaneous cluster headache.[17]

The hypothalamic activation found in our study is more anterior than the region described in cluster headaches and TACs and not lateralized. However, as is true for all PET studies, a lack of anatomical resolution prevents us from localizing individual nuclei within the hypothalamus and brainstem, and prevents us from identifying which side of these structures is involved. Nor can we determine whether the observed increases in regional cerebral blood flow represent excitation, inhibition, or any other energy-consuming process. Moreover, functional imaging techniques highlight regions of physiological activity, but cannot provide directional information about the ascending or descending nociceptive or other inputs from which these changes result.

What is the significance of the hypothalamic activation seen with migraine in this study? We propose 2 alternatives. The first is that hypothalamic activation simply reflects the general processing of painful stimuli. The hypothalamus, along with the periaqueductal gray matter and ventral tegmental area, form part of a functional network that controls the autonomic and nociceptive components of pain. The role of hypothalamus in antinociception has been demonstrated in animals experiences.[18,19] Few PET studies in humans showed hypothalamic activation during traumatic nociceptive pain,[20] angina pectoris,[21] chronic facial pain,[22] or prolonged painful cold stimulation.[23] The second possibility is that the hypothalamic activation observed in our study is more specific. Concerning pain originating from the head, hypothalamic orexigenic mechanisms could play a key role in nociception via modulation of dural nociceptive inputs that are thought to be at the origin of migrainous pain.[24] The importance of orexigenic mechanisms is stressed by their role in hypothalamic regulation of feeding, arousal, and interestingly in regulation of autonomic system and subsequently represents the link between pain and other symptoms found in primary headaches. Therefore, hypothalamic involvement in the pathogenesis of migraine could be more specific than just as a component of nociceptive pathways.

Clinical observations have suggested a role for the hypothalamus in the initiation of migraine attacks. Many of the premonitory symptoms seen up to 48 hours before the onset of headache are regulated by the hypothalamus. These symptoms include sleep disturbances,[25] changes in wakefulness and alertness,[26] changes in mood, craving for food, thirst, and fluid retention.[27,28] Other arguments for the hypothalamic initiation of migraine attacks are: (a) the circadian rhythmicity of the onset of migraine attacks, with a peak incidence in the early morning,[29] (b) the fact that sleep disturbances (insomnia or prolonged sleep) are migraine precipitants,[30] and (c) the correlation of hormonal fluctuations with migraine frequency in females.[31] Neuroendocrine studies suggest also hypothalamic dysfunction in migraine. Patients with chronic migraine also have abnormal patterns of hormonal secretion, including a diminished nocturnal prolactin peak, increased cortisol levels, and a phase delay in the nocturnal melatonin peak.[32] Melatonin levels were also reported to be lower during episodes of headache in patients with episodic or menstrual migraine[33,34] and in chronic migraine with insomnia.[32]

The activation of the hypothalamic and brainstem nuclei persisted after our subjects' headaches had been relieved by sumatriptan. If the hypothalamus acts as a generator of migraine, its activation may continue despite downstream disruption of the nociceptive process by sumatriptan. This may explain the frequent recurrence of migraine attacks when sumatriptan ceases to act on the peripheral trigeminovascular system.[1] The persistence of hypothalamus activation after sumatriptan has relieved the pain can also be interpreted instead of the activation of a generator as the persistent activation of an antinociceptive mechanism, or both.

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