Functional connectivity studies in migraine: what have we learned?

DOI: https://doi.org/10.1186/s10194- 019- 1047- 3

Abstract-Summary Resting-state functional connectivity (FC) MRI has widely been used to understand migraine pathophysiology and to identify an imaging marker of the disorder.

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.

3.4 Neuroimaging

537

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, pre- frontal cortex, salience, somatosensory cortex I, thalamus and visual) were reported. 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.

Extended: We wish to provide an overview of all published conventional resting-

state FC studies and discuss what we have learned so far based on FC findings.

Future FC studies should either pool existing data to extract information about sub-phenotypes of migraine patients or follow guidelines similar to RCT guidelines in case of design of new FC studies.

Introduction An often-used imaging technique is the resting-state or the so-called functional con- nectivity (FC) magnetic resonance imaging (fMRI), which has been applied in increasing number of migraine studies, since the first paper was published in 2011 [339].

Resting-state FC studies may be used to unveil migraine mechanisms. The migraine resting-state literature is often analyzed and presented in several different ways, which makes it hard to compare results across studies, and findings are at times difficult to understand and are rarely reproduced.

We wish to provide an overview of all published conventional resting-state FC

studies and discuss what we have learned so far based on FC findings.

Methods 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.

We used the following search terms: #1 resting state fMRI and migraine, #2 functional connectivity and migraine, and #3 functional connectivity fMRI and migraine.

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.

The higher the degree of synchronization of signal frequency between two differ-

ent voxels, the more functional connected are these voxels, and vice versa.

Brain areas displaying a particular level of similarity represent a functional con-

nectivity network.

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 popula- tion samples.

538

3 Diagnosis

Results Our search strategy was finalized September 20th, 2018 and resulted in a total of 219 results, including 94 unique results, from which following were excluded: 15 reviews, 12 stimulation studies, nine non-conventional FC modalities, six exam- ining effect of treatment (acupuncture), five non-migraine studies, five non-FC studies, four non-original articles, one pediatric study, and one study was retracted.

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.

Three conventional resting-state FC studies (one MA and two MO) have been

published during compared to outside of migraine attacks.

Discussion First systematic review of isolated conventional FC studies in migraine, we report that several areas and networks throughout the brain, brainstem and cerebellum showed altered connectivity in interictal and ictal migraine studies.

In recent resting-state fMRI studies supplementary analyses like the Granger causality [340–342] have been introduced to investigate if FC changes can be linked to migraine phenotypes in the examined populations, but even here findings cannot be reproduced.

None of the reported FC changes may be specific for migraine as other studies reported similar or exact same network changes in several other conditions, includ- ing fibromyalgia [343], Parkinsonian syndromes [344, 345] altered consciousness states [346], systemic lupus [347] and chronic hepatitis C virus infection [348].

The FC method may be useful for the study of specific sub-types of migraine if these are clearly selected beforehand, preferable based on a calculation of the neces- sary number of patients, and with a clear hypothesis to be tested.

Conclusions Imaging, including FC studies could potentially help improve our understanding of underlying disease mechanisms, but so far no reproducible biomarkers of migraine have been identified.

Future FC studies should either pool existing data to extract information about sub-phenotypes of migraine patients or follow guidelines similar to RCT guidelines in case of design of new FC studies.

Acknowledgement A machine generated summary based on the work of Skorobogatykh, Kirill; van Hoogstraten, Willem Sebastiaan; Degan, Diana; Prischepa, Anastasia; Savitskaya, Anastasya; Ileen, Biondo Michela; Bentivegna, Enrico; Skiba, Iaroslav; D’Acunto, Laura; Ferri, Livia; Sacco, Simona; Hansen, Jakob Møller; Amin, Faisal Mohammad; 2019 in The Journal of Headache and Pain.

3.4 Neuroimaging

539

Neuroimaging clues of migraine aura