Disconnectome of the migraine brain: a “connectopathy” model

DOI: https://doi.org/10.1186/s10194- 021- 01315- 6

Abstract-Summary We hypothesize a rearrangement of the brain connectome with an increase of both strength and density of connections between cortical areas specifically involved in pain perception, processing and modulation in migraine patients.

Such connectome rearrangement, inducing an imbalance between the competing parameters of network efficiency and segregation, may underpin a mismatch between energy resources and demand representing the neuronal correlate of the energetically dysfunctional migraine brain.

We investigated, using diffusion-weighted MRI imaging tractography-based graph analysis, the graph-topological indices of the brain “connectome”, a set of grey matter regions (nodes) structurally connected by white matter paths (edges) in 94 patients with migraine without aura compared to 91 healthy controls.

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We observed in migraine patients compared to healthy controls: (1) higher local and global network efficiency (p < 0.001) and (2) higher local and global clustering coefficient (p < 0.001).

We found higher connection (edges) probability between cortical nodes involved in pain perception and modulation as well as in cognitive and affective attribution of pain experiences, in migraine patients when compared to healthy controls (p < 0.001).

The imbalance between the need of investing resources to promote network effi- ciency and the need of minimizing the metabolic cost of wiring probably represents the mechanism underlying migraine patients’ susceptibility to triggers.

Extended: Based on the well-known stability of structural connectome compared to fleeting functional connectome fluctuations, we believe that our findings could be not influenced by the distance from migraine attacks [365].

Future prospective advanced neuroimaging studies remain of paramount impor- tance to further clarify whether observed structural disconnectivity could represent an innate characteristic of migraine brain or the result of a remodelling process induced by the experience of repetitive migraine attacks.

Introduction Decade a plethora of studies has been conducted to explore resting-state functional connectivity (RS-FC) of the brain networks in migraine however conflicting results emerged due several issue such as low homogeneity of patient populations, different methodological approaches and the extreme variability and susceptibility of signal fluctuations across the course of RS-FC scan.

The structural substrates enabling the functional communications among the brain network or connectome, characterized by high stability and reproducibility, have not been widely investigated in migraine [366].

We hypothesize that migraine patients may show a rearrangement of the brain connectome exhibiting increase both strength and density of connections, specifi- cally affecting the nodes involved in multidimensional pain processing with a con- sequent reorganization of hubs topography.

Due to the high energetic resources needed to promote network integration and segregation, we further hypothesize this pattern of brain connectome rearrangement may represent the neuronal correlate of the well-known energetic dysfunction of migraine brain.

Materials and Methods For each group data set (MwoA and HC), a corrected p < 0.05 was deemed to have a connection with the node pair surviving.

Measures of node centrality: Node degree: quantifies the number of connections

that link a node to the rest of the network.

This is a fundamental network measure since most other measures are ultimately linked to node degree; Node strength: is the sum of weights of links connected to the node; Betweenness centrality: is the fraction of all shortest paths in the network that contain a given node.

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It was used to measure a between-group difference using intensity of network connectivity values comprising pairs of regions with FDR correction for multiple comparisons.

For each nodal and global measures, the null hypothesis MwoA  =  HC was tested using a t-test and was rejected at p < 0.05 for all network measures consid- ered and false discovery rate for multiple hypothesis testing correction for all net- work nodes.

Results There was no significant difference between the two groups (94 patients with MwoA and 91 HC) regarding age and male/female ratio.

The distribution of hubs across the whole connectome was similar between data- sets derived from two groups, except for the right posterior cingulate cortex (PCC) and left inferior parietal lobule (IPL) (based on the AAL atlas) identified as hubs only in MwoA patients-derived matrices.

Discussion Findings of nodes centrality showed an overall increase in the values of connection probability by edges, across numerous pairs of anatomical regions, and identified as hubs right PCC and left IPL only in MwoA patients and left calcarine cortex and right OFC only in HC, when comparing the two groups data sets.

This finding is in line with previous pivotal electroencephalographic, magneto- encephalographic and MRI observations that showed an increased clustering coef- ficient in a restricted cohort of migraine patients, due to increased structural and functional local connections among pain-related brain regions inducing a substan- tial reorganization of cortical networks [367–372].

The increased efficiency, clustering and strength of both nodes and their connec- tions observed in migraine patients underpin a non-linear increase in energy demand to manage the large flow of internal and external inputs, justifying increased energy requirements and greater brain vulnerability to stressors.

Conclusion We suggest a new stimulating pathophysiological interpretation model of migraine as a “connectopathy”.

Future prospective advanced neuroimaging studies remain of paramount impor- tance to further clarify whether observed structural disconnectivity could represent an innate characteristic of migraine brain or the result of a remodelling process induced by the experience of repetitive migraine attacks.

Acknowledgement A machine generated summary based on the work of Silvestro, Marcello; Tessitore, Alessandro; Caiazzo, Giuseppina; di Clemente, Fabrizio Scotto; Trojsi, Francesca; Cirillo, Mario; Esposito, Fabrizio; Tedeschi, Gioacchino; Russo, Antonio. 2021 in The Journal of Headache and Pain.

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Altered structural brain network topology in chronic migraine