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Hypothalamic Activation in Spontaneous Migraine Attacks

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Hypothalamic Activation in Spontaneous Migraine Attacks

 

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

 

Abstract

Background: Migraine sufferers experience premonitory symptoms which suggest that primary hypothalamic dysfunction is a likely trigger of the attacks. Neuroendocrine and laboratory data also support this hypothesis. To date, positron emission tomography (PET) scans of migraine sufferers have demonstrated activation of brainstem nuclei, but not of the hypothalamus.

Objective: To record cerebral activations with H215O PET during spontaneous migraine without aura attacks.

Methods: We scanned 7 patients with migraine without aura (6 females and 1 male) in each of 3 situations: within 4 hours of headache onset, after headache relief by sumatriptan injection (between the fourth and the sixth hour after headache onset), and during an attack-free period.

Results: During the headache we found not only significant activations in the midbrain and pons, but also in the hypothalamus, all persisting after headache relief by sumatriptan.

Conclusion: Hypothalamic activity, long suspected by clinical and experimental arguments as a possible trigger for migraine, is demonstrated for the first time during spontaneous attacks.

 

Introduction

Functional imaging with positron emission tomography (PET) or functional MRI (fMRI) has led to a reappraisal of the pathophysiology of primary headaches, particularly in migraine and cluster headache. The main difficulty with functional imaging in an episodic disorder is to capture rare, spontaneous attacks when the imaging techniques require considerable planning. This situation explains the scarcity of functional imaging during spontaneous attacks of migraine. There are only 2 PET studies of spontaneous migraine attacks. Weiller and colleagues scanned 9 subjects with right-sided migraine without aura within 6 hours of the onset of spontaneous migraine headache and after treatment with sumatriptan.[1] The study showed brainstem activation during migraine that persisted after sumatriptan injection and headache resolution. Recently, Afridi and colleagues also found brainstem activation in 5 patients scanned within 24 hours of onset of migraine. Two of the patients in this study had auras before the headache.[2]

 

In other studies, migraine headaches were provoked. Twenty-four subjects were studied with PET from the earliest point of a migraine headaches induced with intravenous glyceryl trinitrate.[3] Activation of dorsolateral pontine nuclei ipsilateral to the headache symptoms were observed. In a BOLD functional MRI study,[4] the purpose was to investigate activation of brainstem structures in patients with visually triggered migraine. Twenty-six patients with migraine (23 with aura and 3 without aura) were studied during repeated checkerboard visual stimulation. An activation of the red nucleus and substantia nigra was found.

 

The fact that migraine headaches begin and end seemingly spontaneously suggests an as-yet-determined trigger. On the basis of functional imaging studies of migraineurs, a role for central brainstem structures as primary "generators" of migraine headaches was proposed.[1,5] Migraine could be caused by episodic dysfunction of those brainstem nuclei that activate a network of cortical and subcortical structures that modulate nociceptive function and vascular control. However, many migraine patients experience before an attack premonitory autonomic and endocrine symptoms (sleep disturbances, changes of wakefulness and alertness, as well as changes of appetite and thirst) that may well be attributed to primary hypothalamic dysfunction.[6] Hypothalamus and interconnected brainstem area could play a key role in migraine physiopathology.

 

By detecting increases in the regional cerebral blood flow (rCBF) in H215O PET, our study sought to determine which brain structures were activated during spontaneous attacks of migraine without aura. The results replicate the brainstem activation found previously and, for the first time, demonstrate activation of the hypothalamus during migraine headaches. This latter finding modifies the current conception of primary headaches.

 

Methods

The local ethics committee approved the study.

 

Patients

Seven patients (6 females and 1 male, mean age: 38.1 years) were studied during a spontaneous, acute migraine attack. All of them fulfilled International Headache Society (IHS) criteria for episodic migraine without aura (ICHD-II code 1.1). None of the patients were undergoing prophylactic treatment. Other medications included the oral contraceptive pill in 4 of the subjects, and thyroxin therapy in 1 subject. All patients came in emergency in the PET center within 4 hours of the onset of migraine symptoms; they were also instructed not to take any triptan or analgesic. Before PET scanning, patients were asked to describe the type and location of their headache, as well as any associated symptoms such as nausea, photophobia, and phonophobia. A pregnancy test was performed in female subjects of childbearing age before each scan. Informed consent was obtained from each patient.

 

PET Scanning

Patients were scanned in 3 conditions (2 scans for each condition): (1) during migraine headache, (2) after headache relief following 6 mg sumatriptan s.c. injection, and (3) during an attack-free interval (15 to 60 days later) (Fig. 1). The time interval between conditions 1 and 2 (the latency of complete headache relief) varied from 20 to 120 minutes. At the end of each scan, the subjects were again asked to rate their headache using a scale from 0 to 10 (0 = no pain, and 10 = the most severe pain imaginable). We confirmed by phone that patients did not have headaches in the 48 hours before and after the attack-free scan.

 

 

Figure 1. (click image to zoom)

Study design.

 

 

 

Data Acquisition

To avoid visual and auditory stimulation, subjects wore opaque goggles while being scanned in a darkened, quiet room. Their head was immobilized, and head position was aligned transaxially to the orbitomeatal line with a laser beam and controlled before each acquisition. PET measurements were performed with a tomograph (EXACT-HR+; CTI-Siemens, Knoxville, TN, USA) that allowed the 3-dimensional acquisition of 63 transaxial slices. Spatial resolution was 4.5mmand 4.1mmin the transaxial and axial directions, respectively.Avenous cannula was inserted to administer tracer, ~350 mBq of H215O, in the left arm. The tracer was infused over 30 seconds at the rate of 6 mL/min. Integrated radioactivity counts were acquired in three 30-second frames beginning 5 to 15 seconds before the peak of the head curve. The interval between 2 scans for a same condition was 8 minutes. A transmission scan was obtained prior to the collection of the emission data for each study to correct for radiation attenuation by tissues in the head.

 

Data Analysis

Image analysis was performed using statistical parametric mapping (SPM2; WellcomeDepartment of Cognitive Neurology, London, UK, http://www.fil.ion.ucl.ac.uk/spm) implemented in MATLAB (Mathworks, Inc., Sherborn, MA, USA). Images of each subject were initially realigned with the reference to the first image to correct for motion artifact and then spatially normalized into a standard stereotaxic space defined by the atlas of Talairach and Tournoux. [7] The normalized images were smoothed with a Gaussian kernel of 8 mm full width at half maximum to account for intersubject differences in anatomy and allow valid statistical inference according to Gaussian random field theory. Statistical parametric maps were generated using an analysis of covariance model after normalization for global cerebral blood flow changes. Because migraine is often characterized by hemicrania, we mirrored the PET scans of the patients with left-sided headache in the sagittal plane. This allowed us to analyze all the patients (3 right hemicranias, 3 left hemicranias, and 1 bilateral headache) in the same analysis. Two comparisons were performed: comparison 1-rCBF during migraine headache versus rCBF during headache free interval; and comparison 2-rCBF after headache relief versus rCBF during headache free interval. All the conditions of activation were coded in order to be processed in SPM in blind condition to avoid a bias effect from the investigator. In accordance with previous studies,[2] we chose a threshold of P < .001 (uncorrected for multiple comparisons) and a cluster extent of >50 voxels for reporting. Our results survived a small volume correction using a 12-mm radius sphere at P < .05 centered on the midbrain, pons, and hypothalamus as reported in the Talairach atlas (respectively, midbrain x = 0, y = -25, z = -10; pons x = 0, y = -27, z = -28; hypothalamus x = 0, y = -2, z = -8).

 

Results

Clinical Data

( Table 1 ) The 7 patients rated their pain as moderate to severe (5 to 9 on a scale from 0 to 10) during the headache phase. Photophobia was present during the attack in all patients, phonophobia in 5, and nausea in 5. The mean time from attack onset to PET scan was 3 h 08 (range 2 h 15 to 3 h 50). We obtained a total headache relief (0 on a scale from 0 to 10) in less than 60 minutes after a single sumatriptan injection in 6 patients.The seventh needed a second injection of sumatriptan and finally an injection of 1 g of aspirin to achieve headache resolution. The postpain relief PET scan was done within 6 hours of headache onset for all patients (from 4 h 20 to 6 hours, mean time 5 h 09).

 

PET Data

During acute migraine attacks (when compared to the headache free scans: comparison 1), we observed significant activations of the hypothalamus and several brainstem areas: the bilateral ventral midbrain, dorsal midbrain controlateral to the headache and the dorso-medial pons (Fig. 2). Activations during headache were also seen in both cerebellar hemispheres, fronto-inferior cortex ipsilateral to the headache (Brodmann areas [bA] 47, 13), and inferior anterocaudal cingulate cortex controlateral to the headache (BA 25) (P < .001, uncorrected for multiple comparison). All the areas of activation seen during headache persisted after treatment, when posttreatment scans were compared to the headache free condition (comparison 2: P < .001, uncorrected for multiple comparison, [Fig. 3]). After small volume correction, the activations of the hypothalamus and the brainstem observed before and after sumatriptan were significant (P = .001, corrected). The coordinates and Z-scores are listed in Table 2 .

 

Comments

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 et al[2] scanned their subjects up to 24 hours post headache onset, a much longer delay than the 4 hour maximum in our study. Weiller et al.'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 ? 4.1 mm).[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] (:o the fact that sleep disturbances (insomnia or prolonged sleep) are migraine precipitants,[30] and © 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.

 

Conclusion

In conclusion, our data replicate activation of midbrain and pons nuclei during spontaneous migraine attacks and, for the first time, demonstrate activation of the hypothalamus. It has long been hypothesized that the prodromal phase of migraine attacks are initiated by a functional disturbance of the hypothalamus, and that either an episodic disturbance of hypothalamic activity or a labile activation threshold could account for the periodicity of the migraine attack.[35-37] Indeed, as early as 1989, Lance hypothesized that internal biological rhythms and/or external triggers such as stressful events and excessive afferent stimulation may initiate a migraine attack via activation of the hypothalamus and its down-stream connections with brainstem nuclei.[36] If the hypothalamus really is the integrator and trigger of migraine attacks, this must be confirmed by the sequential neuroimaging of spontaneous attacks from the prodromal phase onward.

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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.

 

Ding, Ding! I think we have a winner!

 

Yes, I'll be printing this article for my new endo. (only if the information is needed, of course)

 

Thanks for posting this! :)

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Thanks for posting!! I'm going to print and share with my docs also as I continue to have these debilatating (sp?) headaches. I have some issues that make me wonder whats up with my hypothalamus . . . like can't control body temp.

 

Hugs

Amy

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