Kuan-Lin Lai

Subtle changes across different migraine phases in resting electroencephalography (EEG) studies are commonly observed in migraine patients and have the potential to aid in clinical diagnosis. However, exploring the dynamic changes of brain activity across the migraine phases are extremely rare and difficult to analyze. This study aimed to longitudinally investigate the EEG spectral characteristics across the migraine phases in a paired EEG study. Ninety-five episodic migraine (EM) patients without aura and 59 control subjects participated in the study, and the resting close-eye EEG signals were recorded from their frontal and occipital regions. The EEG signals, recorded using a wireless EEG device with three dry spring-loaded electrodes, were retrospectively divided based on the migraine phases and paired after being transformed into wavelet spectra, resulting in 53 interictal-preictal pairs and 17 interictal-ictal pairs. The delta band power of the migraine patients in the frontal region showed that the preictal power, which was comparable to the control subjects, was significantly lower than that of the interictal (ρ < 0.01) and ictal powers. Alternatively, the alpha band power in the occipital region exhibited significantly (ρ < 0.01) higher ictal power compared to the interictal phase but exhibited no significance with preictal condition. The results further showed that 32 out of 46 pairs (69.5%) displayed reduction of frontal delta power from interictal to preictal phase and 11 out of 14 pairs (78.5%) produced increased occipital alpha power from interictal to ictal phase. Further, the low-frequency valley (LFV) power ratio from interictal to preictal phase in frontal region showed a negative correlation with the average headache intensity (AHI) and the domain alpha peak (DAP) power ratio from interictal to ictal phase in occipital region showed a positive correlation with the current headache intensity (CHI). In this longitudinal paired study, our findings suggested that the resting EEG activity efficiently extracted the phase specific spectral characteristics across the migraine patients and obtained significant correlation with the pain intensity levels. Overall, the decreased frontal delta power in the preictal phase and the increased occipital alpha power in the ictal phase may be considered as the potential markers to predict the incoming migraine attack and to quantitatively assess the headache intensity.

Objective: Chronic migraine (CM), characterized by headaches on 15 or more days per month, imposes a substantial burden on daily functioning. Although electroencephalography (EEG) shows promise for detecting subtle migraine-related neural signals, data-driven approaches are often hampered by noisy labels arising from diagnostic bias, annotation errors, data collection challenges, and signal instability, ultimately diminishing data representativeness and limiting their generalizability. Methods: This study presents REAL, a robust EEG analysis and labeling framework integrating (1) global feature extraction via contrastive learning for capturing shared representations, (2) local feature extraction to consolidate within-subject segments, and (3) iterative noisy-label filtering to remove unreliable data. Results: Empirical evaluations indicate that REAL effectively identifies low-confidence samples, presumed to stem from noisy labels, and boosts classification performance, particularly in differentiating CM from healthy controls (CTL). The heterogeneity between low- and high-confidence data has been underscored by label-flipping experiments. Additionally, a marked difference between CTL and CM has been revealed by an entropy-based analysis of high-confidence samples, with higher entropy in CM potentially reflecting an excitatory-inhibitory imbalance and offering deeper insights into CM mechanisms. Conclusion: Comparisons with existing methods underscore REAL's superior ability to handle noisy labels and preserve discriminative features in EEG signals. Significance: These findings highlight REAL's potential to mitigate label noise, advancing EEG-based migraine research and aiding the development of reliable diagnostic tools for clinical practice. By improving data integrity and capturing subtle neural signatures, the effects of noisy labels are mitigated by REAL, thereby supporting accurate migraine detection.

Clinical and preclinical evidence suggests an association between higher levels of IL-6 and migraine. The present study aimed to determine whether pretreatment serum IL-6 levels were associated with headache outcomes at month 3 following migraine preventive treatment. In this prospective study, newly diagnosed migraine patients without current or recent use of preventive medications within 3 months were recruited, and were dichotomized as having higher or lower IL-6 serum levels according to the median at baseline among all of the patients who started preventive treatment with flunarizine. Primary and secondary outcomes were the mean change from baseline in the number of monthly headache days (MHDs) at month 3 based on headache diaries, and the percentage of non-responders, i.e., patients without ≥ 50% MHD reduction at month 3 compared to baseline, respectively. Logistic regression analysis was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) for the association between higher IL-6 levels and treatment non-response, which were further controlled for demographics, headache profiles, disability (measured by Migraine Disability Assessment), psychiatric comorbidities (measured by Hospital Anxiety and Depression Scale), and sleep quality (measured by Pittsburgh Sleep Quality Index). In total, 236 migraine patients (187 F/49 M, mean age ± standard deviation 37.1 ± 10.3 years) were analyzed. At baseline, the median IL-6 level was 0.79 pg/mL, and a higher IL-6 level was associated with an older age (mean age 39.5 ± 10.6 vs. 34.6 ± 9.5 years, p < 0.001) and female sex (85.6% vs. 72.9%, p = 0.016), and a trend toward more MHDs (17.1 ± 8.1 vs. 15.0 ± 8.1 days/month, p = 0.050). After preventive treatment, patients with higher baseline IL-6 levels had less improvement in headache frequency (-5.7 vs. -8.2 MHDs, p = 0.004), and were more likely to be non-responders (72.0% vs. 44.9%, p < 0.001) (adjusted OR = 2.90, 95% CI = 1.61–5.25, p < 0.001). The results were consistent in sensitivity analysis across different subgroups. There was an independent association between higher pretreatment IL-6 levels and poorer response to preventive treatment with flunarizine at month 3 in this large cohort of migraine patients. Whether this finding could be generalizable to other preventives and whether such patients could benefit from preventives of immunomodulatory properties need to be further explored. ClinicalTrials.gov. NCT02747940, NCT04702971.

Background: Inter-regional covariation in grey-matter (GM) structure may provide insights into disease mechanisms. Given that migraine with aura (MA) has been linked to occipital GM alterations, it is plausible that altered occipital GM covariance may also exist in MA. Methods: Structural magnetic resonance images were obtained from 50 MA patients, 50 migraine patients without aura (MO) and 50 healthy controls (HC). Mean GM densities were extracted according to the Automated Anatomical Labeling atlas and regional and global network metrics were compared among the three groups. The local measures primarily focused on occipital regions. We further examined whether voxel-wise covariance of the significant regions was associated with clinical parameters. Results: Increased nodal degree was observed in the right lingual gyrus in MA when compared with HC (p < 0.001, p( _FDR ) = 0.018) and MO (p = 0.005, p( _FDR ) = 0.059), though the latter did not pass correction. In MA, the right lingual gyrus was identified as a hub region and its covariance with the right posterior insula and the left ventral postcentral gyrus was negatively correlated with migraine duration. Global network measures did not differ among the groups. Conclusion: MA was associated with localized changes in the GM-network of the visual system, which may interact with pain-related brain regions depending on the duration of the disorder.

Originally thought to be incurable, huge therapeutic progress has been made in recent years in the field of inherited neuromuscular disorders. Approaches aiming to rescue the underlying pathophysiology, i.e. loss-of-function or gain-of-function mutations, have been developed via end-product replacement or gene delivery/modulation, with promising results. In the review, advanced treatment in some of the inherited neuromuscular disorders will be discussed. On the other hand, it has been found more than 1000 genes are responsible for the clinical diversities in this group of diseases, and finding a way which owns the therapeutic potential to various diseases is the optimal goal. The discovery of CRISPR-Cas9 system in the last decade offers such an opportunity and is under rigorous investigation. This important issue will also be discussed.

Objective: To compare the real‐world effectiveness and tolerability of calcitonin gene‐related peptide (CGRP) monoclonal antibodies (mAbs) and onabotulinumtoxinA in chronic migraine (CM) patients.Methods: This multicenter study involved retrospective analysis of prospectively collected data of CM patients treated with CGRP mAbs or onabotulinumtoxinA, including difficult‐to‐treat (DTT) patients (i.e., ≥3 preventive failures). Treatment outcomes were determined at 6 months based on prospective headache diaries and Migraine Disability Assessment (MIDAS).Results: The study included 316 (55 M/261F, mean age 44.4 ± 13.5 years) and 333 (61 M/272F, mean age 47.9 ± 13.4 years) CM patients treated with CGRP mAbs or onabotulinbumtoxinA, respectively. At 6 months, CGRP mAb treatment was associated with a greater decrease in monthly migraine days (MMDs) (−13.0 vs. −8.7 days/month, p < 0.001) and a higher ≥50% responder rate (RR) (74.7% vs. 50.7%, p < 0.001) compared with onabotulinumtoxinA injections. The findings were consistent in DTT patients (−13.0 vs. −9.1 MMDs, p < 0.001; ≥50% RR: 73.9% vs. 50.3%, p < 0.001) or those with medication‐overuse headache (MOH) (−13.3 vs. −9.0 MMDs, p < 0.001; ≥50% RR: 79.0% vs. 51.6%, p < 0.001). Besides, patients receiving CGRP mAbs had greater improvement (−42.2 vs. −11.8, p < 0.001) and a higher ≥50% RR (62.0% vs. 40.0%, p = 0.001) in MIDAS scores and a lower rate of adverse events (AEs) (6.0% vs. 21.0%, p < 0.001). However, none of the patients discontinued treatment due to AEs.Conclusions: In this multicenter, real‐world study, CGRP mAbs were more effective than onabotulinumtoxinA in CM patients, even in DTT or MOH patients. All of these injectables were well tolerated. Further prospective studies are needed to verify these findings.

Background: The visual cortex is involved in the generation of migraine aura. Voxel-based multivariate analyses applied to this region may provide complementary information about aura mechanisms relative to the commonly used mass-univariate analyses. Methods: Structural images constrained within the functional resting-state visual networks were obtained in migraine patients with (n = 50) and without (n = 50) visual aura and healthy controls (n = 50). The masked images entered a multivariate analysis in which Gaussian process classification was used to generate pairwise models. Generalizability was assessed by five-fold cross-validation and non-parametric permutation tests were used to estimate significance levels. A univariate voxel-based morphometry analysis was also performed. Results: A multivariate pattern of grey matter voxels within the ventral medial visual network contained significant information related to the diagnosis of migraine with visual aura (aura vs. healthy controls: classification accuracy = 78%, p < 0.001; area under the curve = 0.84, p < 0.001; migraine with aura vs. without aura: classification accuracy = 71%, p < 0.001; area under the curve = 0.73, p < 0.003). Furthermore, patients with visual aura exhibited increased grey matter volume in the medial occipital cortex compared to the two other groups. Conclusions: Migraine with visual aura is characterized by multivariate and univariate patterns of grey matter changes within the medial occipital cortex that have discriminative power and may reflect pathological mechanisms.

Aim: This study aimed to investigate the extent of autonomic nervous system dysfunction in patients with chronic migraine using heart rate variability analysis. In addition, we explored the potential association between heart rate variability and treatment outcomes in patients receiving preventive treatment. Methods: In this cross-sectional and prospective study, we compared heart rate variability profiles in 81 preventive-naïve chronic migraine patients and 58 healthy controls. In addition, treatment responses of patients, who received a 12-week treatment with flunarizine, were assessed in relation to baseline heart rate variability. Results: We observed that chronic migraine patients had a reduced heart rate variability, signifying autonomic dysfunction in comparison to healthy controls. Furthermore, patients presenting normal heart rate variability, characterized by a standard deviation exceeding 30 milliseconds in normal-to-normal RR intervals, experienced a superior response to flunarizine treatment. This improvement was exemplified by a significantly larger reduction in monthly headache days for patients with higher heart rate variability compared to those with lower heart rate variability: −9.7 (5.9) vs. −6.2 (6.0) days ( p = .026). Conclusions: Autonomic dysfunction occurs in chronic migraine as evaluated by heart rate variability. A preserved function is associated with a better treatment outcome to flunarizine. Trial registration: Neurologic Signatures of Chronic Pain Disorders, NCT02747940. Registered 22 April 2016, https://clinicaltrials.gov/ct2/show/NCT02747940