Functional connectivity studies in migraine: what have we learned?

Two authors (JMH and FMA) performed search on the PubMed.com website to identify all original articles with resting-state FC data in migraine patients. The literature search was finalized on Pubmed.com September 20th, 2018. We used the following search terms: #1 resting state fMRI and migraine, #2 functional connectivity and migraine, and #3 functional connectivity fMRI and migraine. The search was restricted to human studies published in English language within 10 years, up to September 20th, 2018. Reviews, pediatric studies, case-reports, all other headache diagnoses and letters were excluded. We also assessed reference lists of the found articles for additional relevant studies. Moreover, we excluded all studies that did not use conventional resting-state analysis but other modalities, e.g. functional connectivity density, Granger causality, amplitude of low-frequency fluctuations, and regional homogeneity. Articles, in which the method was not properly described or if data on the comparison to a non-headache control group was not available were also excluded (expect if migraine attacks were compared to an interictal phase). Finally, studies testing treatment effect were also excluded. These exclusion criteria were chosen to include comparable studies in this review.

To screen for inclusion and exclusion criteria, the senior authors (JMH and FMA) assessed all abstracts found in the initial search. The selected studies were then sent to the co-authors (KS, WSvH, DD, AP, AS, BMI, EB, IS, LDA, and LF) who then read the text and extracted further information, i.e. origin of study, study population, method and main findings.

The imaging method is based on blood-oxygen-level dependent (BOLD) recordings of the resting brain (i.e. the person lying in the MRI scanner is relaxing with closed eyes, but not sleeping). Every voxel in the obtained image of the brain emits a signal with a specific frequency. The higher the degree of synchronization of signal frequency between two different voxels, the more functional connected are these voxels, and vice versa. Brain areas displaying a particular level of similarity represent a functional connectivity network. Thus, all areas in the brain are more or less functionally connected to each other. The use of this method depends on the change in the functional connectivity between areas in a network, when measured in two different conditions or population samples.

Twenty-five published studies reported data comparing interictal migraine with non-migraine non-headache controls. In 12 studies a migraine without aura (MO) population was examined, while pure migraine with aura (MA) was only investigated in a single study. In four studies, data for both MA and MO groups were reported separately, whereas mixed results were reported in the remaining eight studies.

When comparing migraine patient to controls, the functional connectivity was changed within or with a number of different networks or seed areas: periaqueductal gray network [1, 23], left [3, 7] dorsal [5] and right [3, 25] anterior cingulate cortex, fronto-parietal-network [4], right occipital lobe [5], left medial [5] and bilateral [7] prefrontal cortex, right cerebellum [5], brainstem [5], bilateral central executive network [6, 20], left [16] salience network [6, 20], default mode network [6, 8, 14, 15, 20, 21], right thalamus [7], right [7] and anterior [9] insula, amygdala [9, 10, 24], bilateral caudate [11], right nucleus accumbens [11], hypothalamus [12], right executive control network [13], left dorsal attention network [16], right cuneus [16], visual network [17], marginal division of neostriatum [18], primary visual cortex [19], primary auditory cortex [19] and bilateral primary somatosensory cortex [26]. All areas with abnormal connectivity to the above-mentioned networks are shown in Table 1 and Additional file 1 and Fig. 2.

Three conventional resting-state FC studies (one MA and two MO) have been published during compared to outside of migraine attacks. Following networks or areas showed altered connectivity during the attack versus outside of the attack: salience network [27], somatosensory network [27], default mode network [27], left pons [28] and right thalamus [29]. All areas with abnormal connectivity to the above-mentioned networks and areas are shown in Table 2.