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      Functional connectivity studies in migraine: what have we learned?

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          Resting-state functional connectivity (FC) MRI has widely been used to understand migraine pathophysiology and to identify an imaging marker of the disorder. Here, we review what we have learned from FC studies.


          We performed a literature search on the PubMed website for original articles reporting data obtained from conventional resting-state FC recording in migraine patients compared with healthy controls or during and outside of migraine attacks in the same patients.


          We found 219 articles and included 28 in this review after screening for inclusion and exclusion criteria. Twenty-five studies compared migraine patients with healthy controls, whereas three studies investigated migraine patients during and outside of attacks. In the studies of interictal migraine more alterations of more than 20 FC networks (including amygdala, caudate nucleus, central executive, cerebellum, cuneus, dorsal attention network, default mode, executive control, fronto-parietal, hypothalamus, insula, neostriatum, nucleus accumbens, occipital lobe, periaqueductal grey, prefrontal cortex, salience, somatosensory cortex I, thalamus and visual) were reported. We found a poor level of reproducibility and no migraine specific pattern across these studies.


          Based on the findings in the present review, it seems very difficult to extract knowledge of migraine pathophysiology or to identify a biomarker of migraine. There is an unmet need of guidelines for resting-state FC studies in migraine, which promote the use of homogenous terminology, public availability of protocol and the a priori hypothesis in line with for instance randomized clinical trial guidelines.

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          Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine.

          The periaqueductal gray matter (PAG), a known modulator of somatic pain transmission, shows evidence of interictal functional and structural abnormalities in migraineurs, which may contribute to hyperexcitability along spinal and trigeminal nociceptive pathways, and lead to the migraine attack. The aim of this study was to examine functional connectivity of the PAG in migraine. Using resting-state functional MRI, we compared functional connectivity between PAG and a subset of brain areas involved in nociceptive/somatosensory processing and pain modulation in 17 subjects with migraine, during a pain-free state, versus 17 gender- and age-matched controls. We also assessed the relation between intrinsic resting-state correlations within PAG networks and the average monthly frequency of migraine attacks, as well as allodynia. Our findings show stronger connectivity between the PAG and several brain areas within nociceptive and somatosensory processing pathways in migraineurs versus controls. In addition, as the monthly frequency of migraine attacks worsens, the strength of the connectivity in some areas within these pathways increases, whereas a significant decrease in functional resting-state connectivity between the PAG and brain regions with a predominant role in pain modulation (prefrontal cortex, anterior cingulate, amygdala) can be evidenced. Finally, migraineurs with a history of allodynia exhibit significantly reduced connectivity between PAG, prefrontal regions, and anterior cingulate compared to migraineurs without allodynia. These data reveal interictal dysfunctional dynamics within pain pathways in migraine manifested as an impairment of the descending pain modulatory circuits, likely leading to loss of pain inhibition, and hyperexcitability primarily in nociceptive areas. Copyright © 2011 American Neurological Association.
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            Functional MRI of migraine.

            Migraine is a disabling neurological condition manifesting with attacks of headache, hypersensitivities to visual, auditory, olfactory and somatosensory stimuli, nausea, and vomiting. Exposure to sensory stimuli, such as odours, visual stimuli, and sounds, commonly triggers migraine attacks, and hypersensitivities to sensory stimuli are prominent during migraine attacks, but can persist with less magnitude between attacks. Functional MRI (fMRI) has been used to investigate the mechanisms that lead to migraine sensory hypersensitivities by measuring brain responses to visual, olfactory, and painful cutaneous stimulation, and functional connectivity analyses have investigated the functional organisation of specific brain regions and networks responsible for sensory processing. These studies have consistently shown atypical brain responses to sensory stimuli, absence of the normal habituating response between attacks, and atypical functional connectivity of sensory processing regions. Identification of the mechanisms that lead to migraine sensory hypersensitivities and that trigger migraine attacks in response to sensory stimuli might help to better understand neural dysfunction in migraine and provide new targets for migraine prevention, and could provide fMRI biomarkers that indicate early responses to preventive therapy.
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              Disrupted default mode network connectivity in migraine without aura

              Background Resting-state functional magnetic resonance imaging (RS-fMRI) has demonstrated disrupted default mode network (DMN) connectivity in a number of pain conditions, including migraine. However, the significance of altered resting-state brain functional connectivity in migraine is still unknown. The present study is aimed to explore DMN functional connectivity in patients with migraine without aura (MwoA) and investigate its clinical significance. Methods To calculate and compare the resting-state functional connectivity of the DMN in 20 patients with MwoA, during the interictal period, and 20 gender- and age-matched HC, Brain Voyager QX was used. Voxel-based morphometry was used to assess whether between-group differences in DMN functional connectivity were related to structural differences. Secondary analyses explored associations between DMN functional connectivity, clinical and neuropsychological features of migraineurs. Results In comparison to HC, patients with MwoA showed decreased connectivity in prefrontal and temporal regions of the DMN. Functional abnormalities were unrelated to detectable structural abnormalities or clinical and neuropsychological features of migraineurs. Conclusions Our study provides further evidence of disrupted DMN connectivity in patients with MwoA. We hypothesize that a DMN dysfunction may be related to behavioural processes such as a maladaptive response to stress which seems to characterize patients with migraine.

                Author and article information

                J Headache Pain
                J Headache Pain
                The Journal of Headache and Pain
                Springer Milan (Milan )
                20 November 2019
                20 November 2019
                : 20
                : 1
                [1 ]University Headache Clinic, Moscow, Russia
                [2 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Neuroscience, , Erasmus MC, ; Rotterdam, The Netherlands
                [3 ]ISNI 0000 0004 1757 2611, GRID grid.158820.6, Department of Applied Clinical Sciences and Biotechnology, , University of L’Aquila, ; L’Aquila, Italy
                [4 ]ISNI 0000 0001 2288 8774, GRID grid.448878.f, Department of Neurology, , Sechenov University, ; Moscow, Russia
                [5 ]GRID grid.7841.a, Sapienza University of Rome, ; Rome, Italy
                [6 ]GRID grid.7841.a, Internal Medicine Unit, Sant’ Andrea Hospital, , Sapienza University of Rome, ; Rome, Italy
                [7 ]ISNI 0000 0004 0562 6029, GRID grid.415628.c, Neurology Department, , Military Medical Academy, ; St. Petersburg, Russia
                [8 ]ISNI 0000 0001 1941 4308, GRID grid.5133.4, Clinical Unit of Neurology, Department of Medical Sciences, , University Hospital and Health Services of Trieste, University of Trieste, ; Trieste, Italy
                [9 ]Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Rome, Italy
                [10 ]ISNI 0000 0004 1757 2611, GRID grid.158820.6, Clinical Neurology Section, Department of Applied Clinical Sciences and Biotechnology, , University of L’Aquila, ; L’Aquila, Italy
                [11 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, , University of Copenhagen, ; Valdemar Hansens Vej 5, Glostrup, 2600 Copenhagen, Denmark
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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