Fibromyalgia (FM) is a disabling chronic pain syndrome with unknown pathophysiology. Functional magnetic resonance imaging studies on FM have suggested altered brain connectivity between the insula and the default mode network (DMN). However, this connectivity change has not been characterized through direct neural signals for exploring the embedded spectrotemporal features and the pertinent clinical relevance. We recorded the resting-state magnetoencephalographic activities of 28 patients with FM and 28 age- and sex-matched controls, and analyzed the source-based functional connectivity between the insula and the DMN at 1–40 Hz by using the minimum norm estimates and imaginary coherence methods. We also measured the connectivity between the DMN and the primary visual (V1) and somatosensory (S1) cortices as intrapatient negative controls. Connectivity measurement was further correlated with the clinical parameters of FM. Compared with the controls, patients with FM reported more tender points (15.2±2.0 vs. 5.9±3.7) and higher total tenderness score (TTS; 29.1±7.0 vs. 7.7±5.5; both p < 0.001); they also had decreased insula–DMN connectivity at the theta band (4–8 Hz; left, p = 0.007; right, p = 0.035), but displayed unchanged V1–DMN and S1–DMN connectivity (p > 0.05). When patients with FM and the controls were combined together, the insula-DMN theta connectivity was negatively correlated with the number of tender points (left insula, r = −0.428, p = 0.001; right insula, r = −0.4, p = 0.002) and TTS score (left insula, r = −0.429, p = 0.001; right insula, r = −0.389, p = 0.003). Furthermore, in patients with FM, the right insula–DMN connectivity at the beta band (13–25 Hz) was negatively correlated with the number of tender points (r = −0.532, p = 0.004) and TTS (r = −0.428, p = 0.023), and the bilateral insula–DMN connectivity at the delta band (1–4 Hz) was negatively correlated with FM Symptom Severity (left: r = −0.423, p = 0.025; right: r = −0.437, p = 0.020) and functional disability (Fibromyalgia Impact Questionnaire; left: r = −0.415, p = 0.028; right: r = −0.374, p = 0.050). We confirmed the frequency-specific reorganization of the insula–DMN connectivity in FM. The clinical relevance of this connectivity change may warrant future studies to elucidate its causal relationship and potential as a neurological signature for FM.

Despite evidently distinct symptoms, tension-type headache (TTH) and migraine are highly comorbid and exhibit many similarities in clinical practice. The purpose of this study was to investigate whether both types of headaches are similar in brain morphology. Consecutive patients with TTH and age- and sex-matched patients with migraine and healthy controls were enrolled for brain magnetic resonance imaging examination. Patients with TTH were excluded if they reported any headache features or associated symptoms of migraine. Changes in gray matter (GM) volume associated with headache diagnosis (TTH vs. migraine) and frequency (episodic vs. chronic) were examined using voxel-based morphometry. The correlation with headache profile and the discriminative ability between TTH and migraine were also investigated for these GM changes. In comparison with controls (n = 43), the patients with TTH (25 episodic and 24 chronic) exhibited a GM volume increase in the anterior cingulate cortex, supramarginal gyrus, temporal pole, lateral occipital cortex, and caudate. The patients with migraine (31 episodic and 25 chronic) conversely exhibited a GM volume decrease in the orbitofrontal cortex. These GM changes did not correlate with any headache profile. A voxel-wise 2 × 2 factorial analysis further revealed the substantial effects of headache types and frequency in the comparison of GM volume between TTH and migraine. Specifically, the migraine group (vs. TTH) had a GM decrease in the superior and middle frontal gyri, cerebellum, dorsal striatum, and precuneus. The chronic group (vs. episodic group) otherwise demonstrated a GM decrease in the bilateral insula and anterior cingulate cortex. In receiver operating characteristic analysis, the GM volumes of the left superior frontal gyrus and right cerebellum V combined had good discriminative ability for distinguishing TTH and migraine (area under the curve = 0.806). TTH and migraine are separate headache disorders with different characteristics in relation to GM changes. The major morphological difference between the two types of headaches is the relative GM decrease of the prefrontal and cerebellar regions in migraine, which may reflect a higher allostatic load associated with this disabling headache.

To investigate the structural changes of hippocampus and amygdala and their relationships with migraine frequency and prognosis. Hippocampus and amygdala volumes were measured by 3-T brain magnetic resonance imaging (MRI) in 31 controls and 122 migraine patients who were categorized into eight groups by headache frequency: group 1 (1–2 headache days/month), 2 (3–4), 3 (5–7), 4 (8–10), 5 (11–14), 6 (15–19), 7 (20–24), and 8 (25–30). Headache frequency was reassessed 2 years later and a frequency reduction ≥50% was regarded a good outcome. Hippocampus and amygdala volumes fluctuated in patient groups but did not differ from the controls. In migraine patients, the bilateral hippocampus volumes peaked in group 3. The volumes and headache frequencies correlated positively in groups 2–3 on bilateral sides (L: r = 0.44, p = 0.007; R: r = 0.35, p = 0.037), and negatively in groups 3–7 on the left side (5–24 days/month; L: r = −0.31, p = 0.004) and groups 3–8 on the right side (r = −0.31, p = 0.002). The left amygdala volume also peaked in group 3, and correlated with headache frequency in groups 1–3 (r = 0.34, p = 0.020) and groups 3–6 (r = −0.30, p = 0.012). The volumetric changes of the right amygdala with headache frequency did not reach statistical significance. At 2-year follow-up, the right hippocampus volume was positively associated with a good migraine outcome after adjustment of headache frequency (OR 4.72, p = 0.024). Hippocampus and amygdala display a structural plasticity linked to both headache frequency and clinical outcome of migraine.

Headaches are universal experiences and among the most common disorders. While headache may be physiological in the acute setting, it can become a pathological and persistent condition. The mechanisms underlying the transition from episodic to chronic pain have been the subject of intense study. Using physiological and imaging methods, researchers have identified a number of different forms of neural plasticity associated with migraine and other headaches, including peripheral and central sensitization, and alterations in the endogenous mechanisms of pain modulation. While these changes have been proposed to contribute to headache and pain chronification, some findings are likely the results of repetitive noxious stimulation, such as atrophy of brain areas involved in pain perception and modulation. In this review, we provide a narrative overview of recent advances on the neuroimaging, electrophysiological and genetic aspects of neural plasticity associated with the most common forms of chronic headaches, including migraine, cluster headache, tension-type headache, and medication overuse headache.

Brain excitability is changed in migraine but not fully characterized yet. This study explored if somatosensory gating is altered in migraine and linked to migraine chronification. Paired electrical stimuli were delivered to the left index fingers of 21 patients with migraine without aura (MO), 22 patients with chronic migraine (CM), and 36 controls. The first and second responses to the paired stimuli were obtained from the contralateral primary (cSI), contralateral secondary (cSII) and ipsilateral secondary (iSII) somatosensory cortices to compute the gating ratios (second vs. first response strengths). The first and second cSI responses and gating ratios differed in all groups (p < 0.05); the responses were typically smaller in the MO and CM groups. The cSI gating ratio increased as a continuum across controls (0.73 ± 0.04, p < 0.001), MO (0.83 ± 0.04) to CM (0.97 ± 0.06) and was higher in CM vs. controls (p < 0.001). When MO and CM were combined, cSI gating ratio was associated with headache frequency (r = 0.418, p = 0.005). Paired responses and gating ratios of cSII and iSII did not differ among the groups. Somatosensory gating is altered in migraine and associated with headache chronification. Further studies must clarify if this abnormal sensory modulation is a true gating deficit independent of low preexcitation level.

Tension-type headache (TTH) and migraine are both common types of headaches. Despite distinct symptoms, TTH and migraine are highly comorbid and exhibit many clinical similarities. This study enrolled consecutive patients with TTH and age- and sex-matched patients with migraine and healthy controls to investigate whether TTH and migraine are similar in brain excitability change assessed by magnetoencephalography. Patients with TTH were excluded if they reported any headache features or associated symptoms of migraine. In response to paired-pulse electrical stimulations, the gating responses obtained from the contralateral primary somatosensory cortex differed between groups. The first response, which reflected the preactivation excitability, was smaller in the migraine group (29.54 ± 2.31 pAm) compared with the TTH group (79.76 ± 8.36, P < 0.001) and controls (59.95 ± 4.26, P = 0.006). The gating ratio (ie, the ratio of the second vs first response strength) was 0.76 ± 0.03 in controls, 0.88 ± 0.03 in the migraine group, 0.93 ± 0.03 in the TTH group, with a significant increase in TTH (P = 0.003 vs controls) suggesting central disinhibition. The area under the receiver operating characteristic curve of the first response strength in differentiating between TTH and migraine was 0.85 ± 0.44, indicating excellent discrimination. In conclusion, TTH and migraine are different clinical entities in view of somatosensory cortex excitability. The preactivation excitability assessed through somatosensory gating is a potential marker for differentiating between TTH and migraine.