Structural and Functional Brain Changes in Migraine

DOI: https://doi.org/10.1007/s40122- 021- 00240- 5

Abstract-Summary Structural and functional changes in the brain of individuals with migraine have been reported.

High frequency of white matter abnormalities, silent infarct-like lesions, and volumetric changes in both gray and white matter in individuals with migraine com- pared to controls have been demonstrated.

Functional magnetic resonance imaging (MRI) studies found altered connectiv-

ity in both the interictal and ictal phase of migraine.

MR spectroscopy and positron emission tomography studies suggest abnormal energy metabolism and mitochondrial dysfunction, as well as other metabolic changes in individuals with migraine.

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Introduction Cortical spreading depolarization (CSD) and abnormal brain stem activity have been shown to be involved in the pathophysiology of migraine with aura [165, 309–311].

Genetic predisposition and its repercussions on brain networks are other known elements underlying the pathophysiology of migraine that have made it possible to better understand the underlying functional alterations [312–315].

Recent evidence from neuroimaging studies including interictal magnetic reso- nance imaging (MRI) shows that migraine pathology may extend beyond migraine pain and can be associated with structural and functional brain changes [316–319]. Migraine changes the brain in ictal and interictal states, resulting in altered mor- phology of cerebral, cerebellar, and brainstem structures, as well as altered neuronal networks and function.

These changes may contribute to the persistently hyperexcitable state in FHM1,

and possibly other types of migraine.

3.4 Neuroimaging

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In the current review, we describe findings from neuroimaging studies on struc-

tural and functional changes in the brain of individuals with migraine.

Structural Changes Neuroimaging studies often reveal white matter hyperintensities or white matter abnormalities (WMAs), silent infarct-like lesions (ILLs), ischemic lesions (stroke), as well as volumetric changes in gray (GM) and white matter (WM) in migraine sufferers [316, 317].

The association between migraine and silent ILLs has been reported in both

clinic-based and population-based studies [316–321].

A high frequency of ILLs in the posterior circulation distribution areas, mostly in the cerebellum, in individuals with migraine with aura compared to those without aura or controls has been reported in two cross-sectional studies [322, 323].

In one cross-sectional study, Kurth and others [324] reported an increased risk of ILLs mostly in deep gray matter, subcortex and the basal ganglia, in individuals with migraine with aura.

To the aforementioned studies, Geist and others [325] did not demonstrate differ- ences in frequency of ILLs between individuals with migraine with aura and controls.

Functional Changes During the interictal phase, alterations have been recognized in more than 20 func- tional connectivity networks in patients with migraine compared to those without migraine, including the default mode network, salience network, frontoparietal net- work, executive network, and sensorimotor network [326].

Some studies suggest differences in interictal alterations of resting state func- tional connectivity between individuals with migraine with and without aura, involving the visual cortex as well as widespread regions involved in visual process- ing (including the middle frontal areas, the insula, the anterior cingulate, the supe- rior parietal lobule, and the cerebellum).

Coppola and others [327] utilized whole-brain independent component analysis during naturally occurring (not medication-induced) migraine attacks and showed decreased functional connectivity between the executive and dorsoventral attention network, when compared to healthy controls, which correlated with attack frequency.

Another study showed decreased overall functional connectivity of the three major intrinsic brain networks (default mode, salience, central executive networks) in women with chronic migraine [328].

Metabolic Changes MRS studies suggest that there is abnormal energy metabolism and mitochondrial dysfunction in patients with migraine, which may decrease the threshold for initiat- ing migraine attacks [329, 330].

Decreased PCr and increased inorganic phosphate, or decreased PCr/inorganic phosphate ratio, were reported in several cortical areas including the occipital cortex

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3 Diagnosis

in patients with migraine with and without aura both during attacks and in the inter- ictal state, when using 31P-MRS [331–334].

These findings, together with reports of decreased interictal GABA levels in the occipital lobe of patients with migraine with and without aura, suggest a predomi- nance of excitatory over inhibitory connections in migraineurs [335, 336].

A recent study [337] using integrated PET/MRI brain scans with [11C]PBR18, a radioligand that binds to the 18 kDa translocator protein (TSPO), demonstrated that patients with migraine interictally and at least 2  weeks following the headache attack had elevated standardized uptake value ratio (SUVR) in their visual cortex as well as the thalamus, primary/secondary somatosensory, and insular cortices.

Perspectives and Conclusions There is increasing evidence for migraine as a potential risk factor for structural and functional changes in the brain.

FMRI studies have shown that individuals with migraine may have atypical neu-

ronal networks and function.

Of the cross-sectional nature of the vast majority of studies, we are still unable to ascertain whether the structural and functional changes in the brain of the individual with migraine are secondary to migraine.

Longitudinal studies are also needed to evaluate how a change in clinical pheno- type of headache such as transformation of episodic to chronic migraine can affect brain imaging findings.

A better understanding of changes in structure and function of brain in individu- als with migraine could help not only in the diagnosis but also in the therapeutic choice [338].

Acknowledgement A machine generated summary based on the work of Ashina, Sait; Bentivegna, Enrico; Martelletti, Paolo; Eikermann-Haerter, Katharina. 2021  in Pain and Therapy.

Functional connectivity studies in migraine: what have we learned?