Introduction

For many people with migraine, their condition is episodic. Without seeing a neurologist or headache specialist and following an appropriate treatment plan, episodic migraine may progress to chronic migraine [1].

The transformation from episodic to chronic migraine occurs when headache is present on 15 or more days per month for more than 3 months, with migraine features on at least 8 days per month. This chronification occurs in approximately 2.5% of migraine patients annually, while reversion from chronic to episodic migraine happens much less frequently [2].

The goal is to prevent the disability associated with chronic migraine by preventing the transformation from episodic to chronic migraine. Moreover, inadequately treating migraine can result in neurological and possibly structural changes [3].

Sensory Changes and Central Sensitization

Patients with chronic migraine experience several neurological changes compared to those with episodic migraine. For example, cutaneous allodynia occurs more frequently in people with chronic migraine versus episodic migraine [5].

An increase in nausea is also more common in chronic migraine patients versus episodic migraine, further contributing to disability [7]. Photophobia and phonophobia have also been linked to the development of chronic migraine and are associated with trigeminal hypersensitivity [8].

Hypothalamic and Brain Network Changes

Studies show changes in the hypothalamus in chronic migraine patients compared to those with episodic migraine [9]. As migraine frequency increases (the defining criteria between episodic and chronic), some brain regions demonstrate heightened activation including areas involved in pain reception, sensory processing, and autonomic regulation while other regions important for executive function and emotion processing show decreased coordination between neural networks [10, 11].

Brain Volume Changes

Changes in brain volume occur as migraine attacks increase in frequency and the disease duration increases [12]:

There is also accumulation of iron in the periaqueductal gray matter, which can potentially serve as a biomarker for chronic migraine [13].

White Matter Lesions

White matter lesions may be visible on MRI in migraine patients. Studies have found that higher attack frequency and longer disease duration positively correlate with white matter lesions [14]. However, this is an increasingly controversial topic as of 2025 with some studies suggesting no relation.

Longitudinal Structural Brain Changes in Migraine

A 2025 study by Planchuelo-Gómez et al. has provided important insights into the long-term evolution of brain structure in migraine patients [31]. This longitudinal study, with follow-up periods between 3-7 years, examined structural changes in both gray matter (GM) and white matter (WM) across different migraine progression patterns.

The research followed three groups of patients: those with stable episodic migraine (EM), those with stable chronic migraine (CM), and those who improved from CM to EM. Using advanced MRI techniques including diffusion tensor imaging and morphometry parameters, the team identified unique structural adaptation patterns associated with different clinical courses [31].

Longitudinal changes were particularly significant in the posterior cingulate gyrus, an area involved in pain processing and perception. Both stable EM and CM groups showed a decrease in cortical thickness in this region (annual relative changes of 0.34% and 0.51% respectively), while patients who improved from CM to EM showed no significant changes [31].

In white matter analysis, patients with stable EM showed increased fractional anisotropy in the cerebral peduncle, a region involved in motor control, sensory relay, and pain processing. These findings suggest that GM is more susceptible to disruption than WM, with the rates of change considerably lower in WM structures [31].

According to Planchuelo-Gómez et al., "The changes observed in regions associated with central pain processing differ from those in other areas related to the migraine experience that are not directly involved in pain processing. Maladaptive changes, which were particularly evident in individuals with 'stable' CM, contrast with adaptive changes seen in those with 'stable' EM." [31]

This longitudinal research provides compelling evidence that the brain adapts differently to stable and changing clinical conditions in migraine, with important implications for understanding disease progression and potentially informing treatment approaches.

Microstructural White Matter and Cortical Gray Matter Changes in Migraine (2025)

A groundbreaking 2025 study by Li et al. published in The Journal of Headache and Pain has revealed important insights into microstructural alterations in both white matter (WM) and cortical gray matter (GM) in migraine patients [32]. This study utilized advanced neuroimaging techniques including Diffusion Tensor Imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI) to investigate microstructural changes at a level not previously possible.

The research team studied 40 chronic migraine patients, 35 episodic migraine patients, and 45 healthy controls using these advanced neuroimaging techniques. Compared to healthy controls, migraine patients showed reduced neurite density in several white matter tracts, including the superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), inferior frontal-occipital fasciculus (IFOF), and uncinate fasciculus (UF) [32].

Chronic migraine patients exhibited more pronounced microstructural damage than those with episodic migraine, showing both reduced neurite density and increased radial diffusivity, suggesting significant axonal demyelination. Notably, these changes were predominantly in the right hemisphere, a finding that warrants further investigation [32].

In the cortical gray matter, migraineurs showed decreased neurites in the right insula and temporal pole cortex, areas involved in pain processing, multisensory integration, and emotional regulation. Patients with chronic migraine specifically demonstrated reduced neurites in the right middle temporal and fusiform cortex [32].

According to Li et al., "Our observed findings support the hypothesis of neuronal remodeling and neurotransmitter alterations in migraine and its subtypes. It provides preliminary evidence for the pathological mechanisms involving impaired brain microstructure and neurotransmitter imbalance following repeated nociception stimuli." [32]

Importantly, the study also investigated the relationship between microstructural changes and neurotransmitter systems, finding that neurite damage in cortical gray matter negatively correlated with several neurotransmitter distributions, including serotonin transporter (SERT), dopamine D2 receptors, dopamine transporter (DAT), and FDOPA. This suggests potential interactions between neurotransmitter imbalances and structural alterations in migraine pathophysiology [32].

Recent Advances in Migraine Neuroimaging

Functional Connectivity Changes

Recent neuroimaging studies have provided deeper insights into the functional differences between chronic and episodic migraine. Research has identified increased connectivity in the pain matrix in chronic migraine patients during the interictal period, using advanced resting-state functional MRI techniques [15]. This suggests persistent alterations in pain processing networks even between attacks in chronic migraine patients. A 2024 study by Frimpong-Manson et al. further characterized these neural pathways, demonstrating how third-order neural projections from the thalamus can undergo aberrant stimulation leading to somatic symptoms of migraine [16].

Prodrome Phase Imaging

Advances in human migraine research, particularly the use of functional imaging techniques lacking radiation exposure, have created exciting opportunities to study the prodrome phase using repeated measures imaging designs. These studies have provided novel insights into attack initiation, migraine neurochemistry, and potential therapeutic targets [17]. Recent work by Karsan (2024) has demonstrated that the ability to scan patients repeatedly with non-invasive imaging modalities has allowed for reproducible imaging of the prodrome phase using nitroglycerin as a trigger [18].

Migraine with Aura Biomarkers

Recent fMRI studies have identified potential biomarkers specific to migraine with aura. A January 2025 study showed that the visual cortex in these patients exhibits distinctive activation patterns, reflecting underlying cortical dysfunction that persists beyond acute episodes, potentially due to chronic neuronal dysregulation or hyperexcitability [19]. This research provides further evidence for cortical spreading depression as a basic mechanism underlying migraine with aura.

Medication Overuse/Adaptation Headache Neuroimaging

A 2025 study by Sun et al. using 7 Tesla multimodal MRI found significant neuroimaging differences between chronic migraine patients with and without medication overuse headache [20]. This advanced imaging approach, combining structural, diffusion tensor, and functional imaging, has characterized distinct brain abnormalities in these patient groups and investigated the relationship between acute analgesic use frequency and these changes. The study demonstrated that medication overuse leads to specific neurobiological alterations that differ from those seen in chronic migraine alone.

Choroid Plexus Volume and Association with Migraine (2025)

A 2025 study by Xiong et al. has identified the choroid plexus as a significant structure in migraine pathophysiology [23]. The research recruited 65 participants (18 with episodic migraine, 16 with chronic migraine, and 31 healthy controls) who underwent brain MRI examinations. The research team used FreeSurfer (Version 7.4.1) software to automatically segment and measure the choroid plexus volume.

Key Findings on Choroid Plexus Volume

• Differential changes in choroid plexus volume: Episodic migraine patients showed decreased choroid plexus to lateral ventricle (CP/LV) ratio, while chronic migraine patients exhibited increased CP/LV ratio compared to controls [23].
• Diagnostic potential: The right-side CP/LV ratio could differentiate episodic migraine from controls with area under the ROC curve (AUC) of 0.696 (95% CI: 0.550-0.818), sensitivity of 100%, and specificity of 46.8%. The diagnostic efficacy was even higher in distinguishing chronic migraine from episodic migraine with AUC of 0.715 (95% CI: 0.536-0.856) [23].
• Correlation with clinical features: Patients with migraine demonstrated increased anxiety, depression, heavier headache burden, and impaired cognitive abilities compared to controls [23].
• Dynamic alterations: The findings suggest dynamic changes in lateral ventricular choroid plexus volume during migraine pathogenesis, with the normalized CP/LV ratio associated with different migraine subtypes [24].

This research suggests that normalized CP/LV measurements could potentially serve as an imaging biomarker for migraine diagnosis and classification. The changes in choroid plexus volume may reflect underlying mechanisms of peripheral-central interaction in migraine, which has been hypothesized but lacked direct evidence until now [23].

Migraine Comorbidities

Besides neurological and anatomical changes, migraine also comes with comorbidities [25]. Increased central sensitization and activation of the trigeminovascular pathway due to migraine play roles in the pathogenesis of other pain syndromes as well.

Frequent migraine attacks result in ongoing inflammation and activation of certain nerve fibers in the trigeminal system. This leads to the release of more CGRP and other neuropeptides that promote inflammation and sensitization of trigeminal nerves [26]. This sensitization leads to changes in pain processing networks in the brain, which in turn leads to migraine chronification and other comorbidities.

Conclusion

Understanding the anatomical and functional consequences of chronic migraine is essential for developing effective prevention and treatment strategies. Recent advances in neuroimaging techniques have revealed complex patterns of brain alterations associated with migraine chronification [27].

The identification of the choroid plexus as a structure involved in migraine pathophysiology opens new avenues for research and potential therapeutic targets [28]. The evidence of dynamic alterations in choroid plexus volume associated with different migraine subtypes may eventually lead to improved diagnostic criteria and personalized treatment approaches.

Longitudinal research by Planchuelo-Gómez et al. has shown that the brain adapts differently to stable versus changing clinical conditions, with patients improving from chronic to episodic migraine showing fewer structural brain changes than those with stable migraine conditions [31]. These findings suggest potential neuroplasticity mechanisms that could be therapeutic targets.

The 2025 microstructural analysis by Li et al. has added a critical new dimension to our understanding, revealing that neurite damage occurs in both white matter and cortical gray matter of migraine patients, with more pronounced damage in chronic migraine [32]. The correlation between these microstructural changes and neurotransmitter systems highlights the complex interplay between structural and neurochemical factors in migraine pathophysiology, offering potential new targets for treatment approaches.

Emerging therapeutic research targeting various pathways, including CGRP, PACAP, and other potential molecular targets, shows promise for migraine prevention and treatment [29]. According to a 2024 publication in The Lancet Neurology, early intervention with targeted therapies may lead to better outcomes for patients [30].

It is crucial to stop the progression from episodic to chronic migraine, as this transformation is associated with significant disability, neuroanatomical changes, and functional alterations. Effective management requires evidence-based approaches rather than unproven "hacks" and misinformation.