We aimed to assess the differences in quantitative sensory testing between chronic migraine and healthy controls and to explore the association between pain sensitivities and outcomes in chronic migraine following preventive treatment.In this prospective open-label study, preventive-naïve chronic migraine and healthy controls were recruited, and cold, heat, mechanical punctate, and pressure pain thresholds over the dermatomes of first branch of trigeminal nerve and first thoracic nerve were measured by quantitative sensory testing at baseline. Chronic migraines were treated with flunarizine and treatment response was defined as ≥50% reduction in the number of monthly headache days over the 12-week treatment period.Eighty-four chronic migraines and fifty age-and-sex-matched healthy controls were included in the analysis. The chronic migraine had higher cold pain thresholds over the dermatomes of the first branch of trigeminal nerve and the first thoracic nerve (p < 0.001 and < 0.001), lower pressure pain thresholds over the dermatomes of the first thoracic nerve (p = 0.003), heat pain thresholds over the dermatomes of the first branch of the trigeminal nerve and the first thoracic nerve (p < 0.001 and p = 0.015) than healthy controls. After treatment, 24/84 chronic migraine had treatment response. The responders with relatively normal pain sensitivity had higher heat pain thresholds over the dermatome of the first branch of the trigeminal nerve (p = 0.002), mechanical punctate pain thresholds over the dermatomes of the first branch of the trigeminal nerve (p = 0.023), and pressure pain thresholds over the dermatomes of the first branch of the trigeminal nerve (p = 0.026) than the hypersensitive non-responders. Decision tree analysis showed that patients with mechanical punctate pain threshold over the dermatomes of the first branch of the trigeminal nerve > 158 g (p = 0.020) or heat pain threshold over the dermatome of the first branch of the trigeminal nerve > 44.9°C (p = 0.002) were more likely to be responders.Chronic migraine were generally more sensitive compared to healthy controls. Preventive treatment with flunarizine should be recommended particularly for chronic migraine who have relatively normal sensitivity to mechanical punctate or heat pain.Trial registration: This study was registered on ClinicalTrials.gov (Identifier: NCT02747940).
We reviewed the studies of mechanical punctate pain thresholds (MPTs) in patients with migraine and summarized their findings focusing on the differences in MPT measurement and MPTs in different phases of migraine.We searched the English-written articles that investigate the MPTs in the migraine population published in peer-reviewed journals with full-text using the PubMed, Web of Science, and Google Scholar databases. Moreover, we manually searched the references from the articles for possibly related studies.We collected 276 articles and finally included twelve studies in this review. Most of the studies that included MPTs were measured with traditional von Frey filaments. The cephalic areas were always included in the assessment. Most studies compared the inter-ictal MPT in patients with migraine to controls. Among them, the majority found no significant differences; however, there were studies found either higher or lower levels of MPTs in migraine. Even though the studies provided the criteria to define the inter-ictal phase, not all of them followed up with the subjects regarding the next migraine attack. In studies that compared MPT between phases, lower MPTs were found during peri-ictal phases.Changes to MPT in migraine patients were inconclusive. The selection of measurement methods as well as properly defined migraine phases should be considered for future studies.
Abstract Background : Chronic migraine (CM) is a disabling headache disorder. Autonomic nervous system (ANS) disturbance, as evidenced from heart rate variability (HRV) studies, has been documented in patients with episodic migraine and other pain disorders but not specifically in patients with CM. This study aimed to explore whether the HRV in patients with CM was impaired and whether it could be used to predict treatment outcomes.Methods : Patients with CM were recruited, along with age- and gender-matched healthy controls (CTLs). The time-domain, frequency-domain, and nonlinear metrics of HRV were calculated to evaluate the sympathetic and parasympathetic aspects of ANS function in patients with CM before and after 3-month (12 weeks) treatment with flunarizine as well as in CTLs. The patients were asked to keep a headache diary throughout the study period to determine the treatment efficacy.Results : A total of 81 patients with CM and 58 CTLs completed the study. Most HRV values in patients with CM were significantly lower than those in CTLs, suggesting decreased overall autonomic modulation and parasympathetic hypofunction but not sympathetic dysfunction. By unsupervised clustering analysis, patients with CM were divided into two cluster groups with high and low HRV at baseline. Patients with high baseline HRV, which was comparable to that of CTLs, showed significantly higher absolute and relative reductions in averaged monthly headache days across a 3-month preventive treatment compared with patients with low baseline HRV (-9.1 days vs. -6.4 days or -43.2% vs. -30.1%, both p < 0.05). The HRV increased after preventive treatment in the low-HRV group but not in the high-HRV group.Conclusions : HRV could distinguish patients with CM from CTLs, indicating the involvement of ANS dysfunction. Moreover, patients with CM having a near-normal baseline HRV, indicating a preserved parasympathetic function and overall ANS modulation reservoir, predicted a better outcome to preventive treatment with flunarizine than those with low HRV.Trial registration: Neurologic Signatures of Chronic Pain Disorders, NCT02747940.Registered 22 April 2016, https://clinicaltrials.gov/ct2/show/NCT02747940
Abstract Pain disorders are associated with aberrant oscillations in the pain-related cortical regions; however, few studies have investigated the relationship between the functional cortical network and migraine chronification through direct neural signals. Magnetoencephalography was used to record the resting-state brain activity of healthy controls as well as patients with episodic migraine (EM) and chronic migraine (CM). The source-based oscillatory dynamics of the pain-related cortical regions, which comprises 10 node regions (the bilateral primary [SI] and secondary somatosensory cortices, insula, medial frontal cortex, and anterior cingulate cortex [ACC]), were calculated to determine the intrinsic connectivity and node strength at 1 to 40 Hz. The total node strength within the pain-related cortical regions was smaller in the beta band in patients with migraine (70 EM and 80 CM) than in controls (n = 65). In the beta band, the node strength and functional connectivity values of patients with CM and patients with EM differed from those of controls in specific cortical areas, notably the left SI (EM < control) and bilateral ACC (CM < control); moreover, the node strength was lower in patients with CM than in those with EM. In all patients with migraine, negative correlations were observed between headache frequency and node strength in the bilateral ACC. In conclusion, migraine is characterized by reduced beta oscillatory connectivity within the pain-related cortical regions. Reduced beta connectivity in the ACC is linked to migraine chronification. Longitudinal studies should verify whether this oscillation change is a brain signature and a potential neuromodulation target for migraine.
Half of the sufferers of reversible cerebral vasoconstriction syndrome (RCVS) exhibit imaging-proven blood-brain barrier disruption. The pathogenesis of blood-brain barrier disruption in RCVS remains unclear and mechanism-specific intervention is lacking. We speculated that cerebrovascular dysregulation might be associated with blood-brain barrier disruption in RCVS. Hence, we aimed to evaluate whether the dynamic cerebral autoregulation is altered in patients with RCVS and could be associated with blood-brain barrier disruption.A cross-sectional study was conducted from 2019 to 2021 at headache clinics of a national tertiary medical center. Dynamic cerebral autoregulation was evaluated in all participants. The capacity of the dynamic cerebral autoregulation to damp the systemic hemodynamic changes, i.e., phase shift and gain between the cerebral blood flow and blood pressure waveforms in the very-low- and low-frequency bands were calculated by transfer function analysis. The mean flow correlation index was also calculated. Patients with RCVS received 3-dimensional isotropic contrast-enhanced T2 fluid-attenuated inversion recovery imaging to visualize blood-brain barrier disruption.Forty-five patients with RCVS (41.9 ± 9.8 years old, 29 females) and 45 matched healthy controls (41.4 ± 12.5 years old, 29 females) completed the study. Nineteen of the patients had blood-brain barrier disruption. Compared to healthy controls, patients with RCVS had poorer dynamic cerebral autoregulation, indicated by higher gain in very-low-frequency band (left: 1.6 ± 0.7, p = 0.001; right: 1.5 ± 0.7, p = 0.003; healthy controls: 1.1 ± 0.4) and higher mean flow correlation index (left: 0.39 ± 0.20, p = 0.040; right: 0.40 ± 0.18, p = 0.017; healthy controls: 0.31 ± 0.17). Moreover, patients with RCVS with blood-brain barrier disruption had worse dynamic cerebral autoregulation, as compared to those without blood-brain barrier disruption, by having less phase shift in very-low- and low-frequency bands, and higher mean flow correlation index.Dysfunctional dynamic cerebral autoregulation was observed in patients with RCVS, particularly in those with blood-brain barrier disruption. These findings suggest that impaired cerebral autoregulation plays a pivotal role in RCVS pathophysiology and may be relevant to complications associated with blood-brain barrier disruption by impaired capacity of maintaining stable cerebral blood flow under fluctuating blood pressure.
Abstract Background Pain sensitivity may determine the risk, severity, prognosis, and efficacy of treatment of clinical pain. Magnetic resonance imaging studies have linked thermal pain sensitivity to changes in brain structure. However, the neural correlates of mechanical pain sensitivity remain to be clarified through investigation of direct neural activities on the resting-state cortical oscillation and synchrony. Methods We recorded the resting-state magnetoencephalographic (MEG) activities of 27 healthy individuals and 30 patients with episodic migraine (EM) and analyzed the source-based oscillatory powers and functional connectivity at 2 to 59 Hz in pain-related cortical regions, which are the bilateral anterior cingulate cortex (ACC), medial orbitofrontal (MOF) cortex, lateral orbitofrontal (LOF) cortex, insula cortex, primary somatosensory cortex (SI), primary motor cortex (MI), and posterior cingulate cortex (PCC). The mechanical punctate pain threshold (MPPT) was obtained at the supraorbital area (the first branch of the trigeminal nerve dermatome, V1) and the forearm (the first thoracic nerve dermatome, T1) and further correlated with MEG measures. Results The MPPT is inversely correlated with the resting-state relative powers of gamma oscillation in healthy individuals (all corrected P < 0.05). Specifically, inverse correlation was noted between the MPPT at V1 and gamma powers in the bilateral insula (r = −0.592 [left] and −0.529 [right]), PCC (r = −0.619 and −0.541) and MI (r = −0.497 and −0.549) and between the MPPT at T1 and powers in the left PCC ( r = −0.561) and bilateral MI ( r = −0.509 and −0.520). Furthermore, resting-state functional connectivity at the delta to beta bands, especially between frontal (MOF, ACC, LOF, and MI), parietal (PCC), and sensorimotor (bilateral SI and MI) regions, showed a positive correlation with the MPPT at V1 and T1 (all corrected P < 0.05). By contrast, in patients with EM, the MPPT was not associated with resting-state cortical activities. Conclusions Pain sensitivity in healthy individuals is associated with the resting-state gamma oscillation and functional connectivity in pain-related cortical regions. Further studies must be conducted in a large population to confirm whether resting-state cortical activities can be an objective measurement of pain sensitivity in individuals without clinical pain.
Objective This study was undertaken to investigate migraine glymphatic and meningeal lymphatic vessel (mLV) functions. Methods Migraine patients and healthy controls (HCs) were prospectively recruited between 2020 and 2023. Diffusion tensor image analysis along the perivascular space (DTI‐ALPS) index for glymphatics and dynamic contrast‐enhanced magnetic resonance imaging parameters (time to peak [TTP]/enhancement integral [EI]/mean time to enhance [MTE]) for para‐superior sagittal (paraSSS)‐mLV or paratransverse sinus (paraTS)‐mLV in episodic migraine (EM), chronic migraine (CM), and CM with and without medication‐overuse headache (MOH) were analyzed. DTI‐ALPS correlations with clinical parameters (migraine severity [numeric rating scale]/disability [Migraine Disability Assessment (MIDAS)]/bodily pain [Widespread Pain Index]/sleep quality [Pittsburgh Sleep Quality Index (PSQI)]) were examined. Results In total, 175 subjects (112 migraine + 63 HCs) were investigated. DTI‐ALPS values were lower in CM (median [interquartile range] = 0.64 [0.12]) than in EM (0.71 [0.13], p = 0.005) and HCs (0.71 [0.09], p = 0.004). CM with MOH (0.63 [0.07]) had lower DTI‐ALPS values than CM without MOH (0.73 [0.12], p < 0.001). Furthermore, CM had longer TTP (paraSSS‐mLV: 55.8 [12.9] vs 40.0 [7.6], p < 0.001; paraTS‐mLV: 51.2 [8.1] vs 44.0 [3.3], p = 0.002), EI (paraSSS‐mLV: 45.5 [42.0] vs 16.1 [9.2], p < 0.001), and MTE (paraSSS‐mLV: 253.7 [6.7] vs 248.4 [13.8], p < 0.001; paraTS‐mLV: 252.0 [6.2] vs 249.7 [1.2], p < 0.001) than EM patients. The MIDAS ( p = 0.002) and PSQI ( p = 0.002) were negatively correlated with DTI‐ALPS index after Bonferroni corrections ( p < q = 0.01). Interpretation CM patients, particularly those with MOH, have glymphatic and meningeal lymphatic dysfunctions, which are highly clinically relevant and may implicate pathogenesis for migraine chronification. ANN NEUROL 2024;95:583–595
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