Table 1.

Imaging appraisal of hypothalamus dysfunction in the premonitory phase of migraine

First Author, Publication Year	Imaging Method	Study Population(s), Sample Size (n)	Definition of the Premonitory Phase	Main Findings	Limitations
Denuelle et al., 2007 [52]	H215O PET	MO, n = 7	No case definition was provided, and the authors did not report whether the participants reported any premonitory symptoms.	Hypothalamic and brainstem activation within the first four hours of spontaneous migraine attacks, persisting after pain relief. The authors suggested hypothalamic involvement in non-painful symptoms.	Patients were not scanned during the premonitory phase. No control group.
Maniyar et al., 2014 [57]	H215O PET	MO, n = 8	Period after cessation of unspecific NTG-induced headache and before migraine headache, when patients started to experience symptoms warning them of an impending headache. These symptoms had to be present on at least two enquiries (initially every 5 min and then every 10–15 minutes).	Hypothalamic activation during the early premonitory phase, but not in the late premonitory phase nor in the headache phase.	Hypothalamic activation was not observed when early and late premonitory phase were pooled together. Lack of definition of the early and late premonitory phase. No placebo control. No control group.
Maniyar et al., 2014 [60]	H215O PET	MO, n = 10		Activation in rostral dorsal medulla and periaqueductal grey matter, but not in hypothalamus, in patients experiencing nausea.	Small sample size of patients with nausea (n = 3). No placebo control. No control group.
Maniyar et al., 2014 [73]	H215O PET	MO, n = 10		Higher activation of extrastriate cortex in patients with photophobia during the premonitory phase of NTG-triggered attacks. No hypothalamic activation.	Small sample size of patients with photophobia (n = 5) No placebo control. No control group.
Schulte et al., 2016 [53]	BOLD fMRI	MO, n = 1	No case definition was provided, and the authors did not report whether the participants reported any premonitory symptoms.	Activation of hypothalamus in the pre-ictal phase. Functional coupling of hypothalamus with spinal trigeminal nucleus, which switch to dorsal pons in the headache phase.	Premonitory symptoms were not reported. Results corresponded to the preictal phase, not the premonitory phase, per se. No control group.
Schulte et al., 2020 [54]	BOLD fMRI	MO, n = 6 MA, n = 1	No case definition was provided, and the authors did not report whether the participants reported any premonitory symptoms.	Hypothalamus activation started 48 hours prior to the headache phase.
Meylakh et al., 2018 [56]	BOLD fMRI	MO, n = 21 MA, n = 5	No case definition was provided. The authors reported that the patients had no predicting factor that they were 24 hours prior to a migraine attack. No definition of the predicting factors.	Increased infra-slow oscillatory power only prior to a migraine attack in the brainstem, thalamus and hypothalamus. Increase functional connectivity between PAG and hypothalamus prior to the migraine attack.	Migraine phases were retrospectively defined and no predictive factors to be in the preictal phase, including premonitory symptoms, were reported. Overall, increased and decreased functional connectivity between hypothalamus and PAG.
Meylakh et al., 2020 [74]	ASL and BOLD fMRI	MO, n = 25 MA, n = 9	No case definition was provided. The authors reported that the patients had no predicting factor that they were 24 hours prior to a migraine attack. No definition of the predicting factors.	Decrease regional cerebral blood flow in the lateral hypothalamus and decrease functional connectivity of lateral hypothalamus with pain processing pathway, including PAG.
Karsan et al., 2020 [58]	BOLD fMRI	MO, n = 10 MA, n = 15	Period with at least 3 symptoms typical for the subject, assessed by questionnaire, after NTG-infusion in the absence of any migraine headache, consistently reported on 2 separate episodes of enquiry.	Several changes in connectivity of thalamus with precuneus and cuneus, pons with limbic lobe, cingulate and frontal cortices in the premonitory phase.	Connectivity of hypothalamus was assessed but not its activity/response to external stimuli. Baseline hypothalamic connectivity was not comparable between active and placebo groups.
Van Oosterhout et al., 2021 [59]	BOLD fMRI	MO, n = 15	Period with at least 1 symptom assessed by questionnaire after NTG-infusion before the onset of a provoked migrainous headache.	Hypothalamic signal recovery phase was abnormally faster and steeper in the premonitory phase of a NTG-triggered and spontaneous attacks, suggesting hypothalamic dysregulation.	Dysregulation was observed in response to a specific hypothalamic activation, not during its spontaneous activity. No placebo control.

ASL Arterial Spin Labelling. BOLD Blood Oxygen Level Dependent. CBF Cerebral Blood Flow. fMRI functional Magnetic Resonance Imaging. HC Healthy Controls. MA Migraine with Aura. MO Migraine without Aura. NTG Nitroglycerin. PAG Periaqueductal Grey Matter. PET Positron Emission Tomography