The normative values of pain thresholds in healthy Taiwanese.

OBJECTIVE: Quantitative sensory testing is widely used in clinical and research settings to assess the sensory functions of healthy subjects and patients. It is of importance to establish normative values in a healthy population to provide reference for studies involving patients. Given the absence of normative values for pain thresholds in Taiwan, the aim of this study was to report the normative values for future reference in the Taiwanese population and compare the differences between male and female participants. METHODS: Healthy adults without any chronic or acute pain condition were recruited. The pain thresholds were assessed over the cephalic (supraorbital area and masseter muscle) and extracephalic (medio-volar forearm and thenar eminence) areas. The heat, cold, mechanical punctate, and pressure pain thresholds were measured with a standardized protocol. Comparisons between male and female participants were performed. RESULTS: One hundred and thirty healthy participants (55 males: 30.4 ± 7.4 years; 75 females: 30.5 ± 8.1 years) finished the assessments. Male participants were less sensitive to mechanical stimuli, including pressure over masseter muscle (male vs. female: 178.5 ± 56.7 vs. 156.6 ± 58.4 kPa, p = .034) and punctate over medio-volar forearm (male vs. female: 116.4 ± 45.2 vs. 98.7 ± 65.4 g, p = .011), compared to female participants. However, female participants were less sensitive to cold stimuli, indicated by lower cold pain thresholds over the supraorbital area (male vs. female: 18.6 ± 8.4 vs. 13.6 ± 9.3°C, p = .004), compared to male participants. No significant differences were found between sexes in other pain threshold parameters. CONCLUSIONS: We provided the normative values of healthy male and female adults in Taiwan. This information is crucial for comparison in future pain-related studies to identify potential hypoalgesia or hyperalgesia of tested subjects.

Dynamic changes in glymphatic function in reversible cerebral vasoconstriction syndrome.

BACKGROUND: The pathophysiology of the reversible cerebral vasoconstriction syndrome (RCVS) remains enigmatic and the role of glymphatics in RCVS pathophysiology has not been evaluated. We aimed to investigate RCVS glymphatic dynamics and its clinical correlates. METHODS: We prospectively evaluated the glymphatic function in RCVS patients, with RCVS subjects and healthy controls (HCs) recruited between August 2020 and November 2023, by calculating diffusion-tensor imaging along the perivascular space (DTI-ALPS) index under a 3-T MRI. Clinical and vascular (transcranial color-coded duplex sonography) investigations were conducted in RCVS subjects. RCVS participants were separated into acute (≤ 30 days) and remission (≥ 90 days) groups by disease onset to MRI interval. The time-trend, acute stage and longitudinal analyses of the DTI-ALPS index were conducted. Correlations between DTI-ALPS index and vascular and clinical parameters were performed. Bonferroni correction was applied to vascular investigations (q = 0.05/11). RESULTS: A total of 138 RCVS patients (mean age, 46.8 years ± 11.8; 128 women) and 42 HCs (mean age, 46.0 years ± 4.5; 35 women) were evaluated. Acute RCVS demonstrated lower DTI-ALPS index than HCs (p < 0.001) and remission RCVS (p < 0.001). A continuously increasing DTI-ALPS trend after disease onset was demonstrated. The DTI-ALPS was lower when the internal carotid arteries resistance index and six-item Headache Impact test scores were higher. In contrast, during 50-100 days after disease onset, the DTI-ALPS index was higher when the middle cerebral artery flow velocity was higher. CONCLUSIONS: Glymphatic function in patients with RCVS exhibited a unique dynamic evolution that was temporally coupled to different vascular indices and headache-related disabilities along the disease course. These findings may provide novel insights into the complex interactions between glymphatic transport, vasomotor control and pain modulation.

Grey matter structure within the visual networks in migraine with aura: multivariate and univariate analyses.

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.

Impaired Glymphatic and Meningeal Lymphatic Functions in Patients with Chronic Migraine.

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.

Association between impaired dynamic cerebral autoregulation and BBB disruption in reversible cerebral vasoconstriction syndrome.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Sex differences in the clinical manifestations related to dependence behaviors in medication-overuse headache.

OBJECTIVE: The present study aimed to compare sex differences in the clinical manifestations related to dependence behaviors in medication-overuse headache (MOH). METHODS: Consecutive patients with newly diagnosed chronic migraine (CM) with and without MOH based on the Third Edition of International Classification of Headache Disorders (ICHD-3) were enrolled prospectively from the headache clinic of a tertiary medical center. Demographics and clinical profiles were collected by using a questionnaire, which included current use of tobacco, alcohol, and caffeinated beverages, the Leeds Dependence Questionnaire (LDQ), the Severity of Dependence Scale (SDS), the Headache Impact Test-6 (HIT-6), and the Pittsburgh Sleep Quality Index (PSQI). RESULTS: In total, 1419 CM patients (1135F/284 M, mean age 41.7 ± 13.9 years) were recruited, including 799 with MOH (640F/159 M, mean age 42.5 ± 13.2 years) (56.3%). Smoking was associated with an increased risk for MOH in men (odds ratio [OR] = 3.60 [95% confidence interval = 1.73-7.50], p = 0.001), but not in women (OR = 1.34 [0.88-2.04], p = 0.171) (p = 0.021 for interaction). Hypnotic use ≥ 3 days/week was a risk factor for MOH (OR = 2.55 [95% confidence interval = 2.00-3.24], p < 0.001), regardless of sex. By using receiver operating characteristics (ROC) curves, the cutoff scores of the LDQ for MOH were determined at 7 for women and 6 for men, and those for the SDS were 5 and 4, respectively (area under curve all ≥ 0.83). Among patients with MOH, the male sex was associated with a shorter latency between migraine onset and CM onset (12.9 ± 11.1 vs. 15.4 ± 11.5 years, p = 0.008), despite less average headache intensity (6.7 ± 1.9 vs. 7.2 ± 1.9, p = 0.005), functional impacts (HIT-6: 63.4 ± 8.3 vs. 65.1 ± 8.0, p = 0.009), and sleep disturbances (PSQI: 10.9 ± 4.4 vs. 12.2 ± 4.3, p = 0.001). CONCLUSIONS: The current study identified an association between smoking and MOH in men, as well as sex-specific cutoffs of the LDQ and the SDS, for MOH. MOH was characterized by a shorter latency between migraine onset and CM onset in men and a more severe phenotype in women. Sex should be considered as an important factor in the evaluation of MOH.

Prolonged headache with vaccine- and dose-specific headache pattern associated with vaccine against SARS-CoV-2 in patients with migraine.

OBJECTIVE: To examine SARS-CoV-2 vaccine-related headache characteristics and risk factors in migraine patients. METHODS: This retrospective cohort study included 732 migraine patients who had AstraZeneca Vaxzevria, Pfizer-BioNTech Comirnaty, or Moderna Spikevax vaccines. Participants provided information through questionnaires and headache diaries. Headache frequency before and after vaccination and factors associated with headache risk were examined. RESULTS: Approximately a third of patients reported increased headache the day after having primary and booster doses, with mean increase ± SD of 1.9 ± 1.2 and 1.8 ± 1.1 days/week, respectively. Proportions of migraine patients with headache (after vaccination vs. before vaccination) increased after having primary-dose Vaxzevria (35.3% vs. 22.8%, p < 0.001) but not Spikevax (23.8% vs. 26.7%, p = 0.700) or Comirnaty (33.2% vs. 25.8%, p = 0.058). Headache proportion increased after having all three boosters (Vaxzevria 27.1% vs. 17.9% p = 0.003; Comirnaty 34.1% vs. 24.5% p = 0.009; Spikevax 35.2% vs. 24.8% p = 0.031). For primary dose with Vaxzevria and Comirnaty, headache risk increased on the vaccination day, peaked on the day after vaccination, and subsided within a week, while for Spikevax headache risk rose gradually after vaccination, peaked on the seventh post-vaccination day and subsided subsequently. For booster dose, headache risk generally increased on the vaccination day, peaked on the day after vaccination, and subsided gradually with fluctuating pattern within a month. Our study also showed that headache increased on the day before primary dose but not booster dose vaccination and it may be attributable to stress associated with having to undertake new vaccines. Multivariable analyses showed that depression was associated with headache. CONCLUSION: Prolonged headache with vaccine- and dose-specific headache pattern was found. Patients with higher risks of vaccine-related headache must be informed of the potential worsening headache.

Abnormal heart rate variability and its application in predicting treatment efficacy in patients with chronic migraine: An exploratory study.

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.

Characteristic oscillatory brain networks for predicting patients with chronic migraine.

To determine specific resting-state network patterns underlying alterations in chronic migraine, we employed oscillatory connectivity and machine learning techniques to distinguish patients with chronic migraine from healthy controls and patients with other pain disorders. This cross-sectional study included 350 participants (70 healthy controls, 100 patients with chronic migraine, 40 patients with chronic migraine with comorbid fibromyalgia, 35 patients with fibromyalgia, 30 patients with chronic tension-type headache, and 75 patients with episodic migraine). We collected resting-state magnetoencephalographic data for analysis. Source-based oscillatory connectivity within each network, including the pain-related network, default mode network, sensorimotor network, visual network, and insula to default mode network, was examined to determine intrinsic connectivity across a frequency range of 1-40 Hz. Features were extracted to establish and validate classification models constructed using machine learning algorithms. The findings indicated that oscillatory connectivity revealed brain network abnormalities in patients with chronic migraine compared with healthy controls, and that oscillatory connectivity exhibited distinct patterns between various pain disorders. After the incorporation of network features, the best classification model demonstrated excellent performance in distinguishing patients with chronic migraine from healthy controls, achieving high accuracy on both training and testing datasets (accuracy > 92.6% and area under the curve > 0.93). Moreover, in validation tests, classification models exhibited high accuracy in discriminating patients with chronic migraine from all other groups of patients (accuracy > 75.7% and area under the curve > 0.8). In conclusion, oscillatory synchrony within the pain-related network and default mode network corresponded to altered neurophysiological processes in patients with chronic migraine. Thus, these networks can serve as pivotal signatures in the model for identifying patients with chronic migraine, providing reliable and generalisable results. This approach may facilitate the objective and individualised diagnosis of migraine.

Treatment pattern and health care resource utilization for Taiwanese patients with migraine: a population-based study.

Objectives: Given the substantial disease burden, appropriate and effective management of migraine is a public health priority. To gain insights into real-world migraine management practices in Taiwan, current treatment patterns, costs, and health care resource use were assessed. Methods: This was a retrospective, longitudinal study using the Taiwan National Health Insurance Research Database. Included patients had an initial diagnosis of migraine (defined using International Classification of Diseases codes) between 1 January 2013 and 31 December 2017. Data analyzed included demographics; the use, number, and type of acute and preventive medications; and drug and medical services costs. Data were stratified according to migraine type (chronic [CM] or episodic [EM] migraine). Results: A total of 312,718 patients were included in the analyses: 53,992 (17.3%) had CM and 258,726 (82.7%) had EM. Most patients (81.7%) had used acute and/or preventive medications; acute medications used more frequently than preventive medications (78.0% vs. 20.2%). Acute medications were used by 81.6 and 77.3% of patients with CM and EM, respectively. Commonly used acute medications were acetaminophen (68.8%), ergots (49.4%), and non-steroidal anti-inflammatory drugs (38.4%); the use of triptans (6.0%), tramadol (3.1%), and other opioids (0.2%) was less common. A total of 28.6 and 18.5% of patients with CM and EM, respectively, used preventive medications. Flunarizine (68.9%), propranolol (40.7%), and topiramate (16.0%) were the most commonly used preventive medications. Most patients had used 1-2 acute or preventive medications, with the use of ≥3 acute or preventive medications more common in patients with CM than EM. Average total medical cost per annum was 4,169 New Taiwan Dollars (NTDs) per CM patient and 2,928 NTDs per EM patient, with CM patients having higher costs associated with medical service utilization and acute medication use. Conclusion: These real-world data suggest unmet needs for Taiwanese patients with migraine, including under-utilization of preventive medications and greater costs and health care resource use for patients with CM versus EM. These findings provide important information on treatment patterns, cost, and health care resource use for patients with migraine in Taiwan.

Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor.

OBJECTIVE: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. METHODS: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. RESULTS: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. INTERPRETATION: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713-726.

Noninvasive investigations of human glymphatic dynamics in a diseased model.

OBJECTIVES: To explore human glymphatic dynamics in a diseased model via a noninvasive technique. METHODS: Patients with reversible vasoconstriction syndrome (RCVS) presenting with blood-brain barrier disruption, i.e., para-arterial gadolinium leakage on 3-T 3-dimensional isotropic contrast-enhanced T2-fluid-attenuated inversion recovery (CE-T2-FLAIR) magnetic resonance imaging (MRI), were prospectively enrolled. Consecutive 9-min-CE-T2-FLAIR for 5-6 times (early panel) after intravenous gadolinium-based contrast agent (GBCA) administration and one time-varying deferred scan of noncontrast T2-FLAIR (delayed panel) were performed. In Bundle 1, we measured the calibrated signal intensities (cSIs) of 10 different anatomical locations. In Bundle 2, brain-wide measurements of para-arterial glymphatic volumes, means, and medians of the signal intensities were conducted. We defined mean (mCoIs) or median (mnCoIs) concentration indices as products of volumes and signal intensities. RESULTS: Eleven subjects were analyzed. The cSIs demonstrated early increase (9 min) in perineural spaces: (cranial nerve [CN] V, p = 0.008; CN VII + VII, p = 0.003), choroid plexus (p = 0.003), white matter (p = 0.004) and parasagittal dura (p = 0.004). The volumes, mCoIs, and mnCoIs demonstrated increasing rates of enhancement after 9 to 18 min and decreasing rates after 45 to 54 min. The GBCA was transported centrifugally and completely removed within 961-1086 min after administration. CONCLUSIONS: The exogenous GBCA leaked into the para-arterial glymphatics could be completely cleared around 961 to 1086 min after administration in a human model of BBB disruption. The tracer enhancement started variously in different intracranial regions but was eventually cleared centrifugally to brain convexity, probably towards glymphatic-meningeal lymphatics exits. CLINICAL RELEVANCE STATEMENT: Glymphatic clearance time intervals and the centrifugal directions assessed by a noninvasive approach may have implications for clinical glymphatic evaluation in the near future. KEY POINTS: • This study aimed to investigate the human glymphatic dynamics in a noninvasive diseased model. • The intracranial MR-detectable gadolinium-based contrast agents were removed centrifugally within 961 to 1086 min. • The glymphatic dynamics was demonstrable by enhancing MRI in an in vivo diseased model noninvasively.

Disrupted Brain Functional Status in Patients with Reversible Cerebral Vasoconstriction Syndrome.

OBJECTIVES: The aim of this study was to investigate the functional networks in subjects with reversible cerebral vasoconstriction syndrome (RCVS) using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: We prospectively recruited patients with RCVS and healthy controls (HCs) between February 2017 and April 2021. The rs-fMRI data were analyzed using graph theory methods. We compared node-based global and regional topological metrics (Bundle 1) and network-based intranetwork and internetwork connectivity (Bundle 2) between RCVS patients and HCs. We also explored the associations of clinical and vascular (ie, the Lindegaard index, LI) parameters with significant rs-fMRI metrics. RESULTS: A total of 104 RCVS patients and 93 HCs were included in the final analysis. We identified significantly decreased local efficiency of the left dorsal anterior insula (dAI; p = 0.0005) in RCVS patients within 30 days after disease onset as compared to HCs, which improved 1 month later. RCVS patients also had increased global efficiency (p = 0.009) and decreased average degree centrality (p = 0.045), clustering coefficient (p = 0.033), and assortativity values (p = 0.003) in node-based analysis. In addition, patients with RCVS had increased internetwork connectivity of the default mode network (DMN) with the salience (p = 0.027) and dorsal attention (p = 0.016) networks. Significant correlations between LI and regional local efficiency in left dAI (rs = -0.418, p = 0.042) was demonstrated. INTERPRETATION: The significantly lower local efficiency of the left dAI, suggestive of impaired central autonomic modulation, was negatively correlated with vasoconstriction severity, which is highly plausible for the pathogenesis of RCVS. ANN NEUROL 2023;94:772-784.

Identification of patients with chronic migraine by using sensory-evoked oscillations from the electroencephalogram classifier.

BACKGROUND: To examine whether the modulating evoked cortical oscillations could be brain signatures among patients with chronic migraine, we investigated cortical modulation using an electroencephalogram with machine learning techniques. METHODS: We directly record evoked electroencephalogram activity during nonpainful, painful, and repetitive painful electrical stimulation tasks. Cortical modulation for experimental pain and habituation processing was analyzed and used to differentiate patients with chronic migraine from healthy controls using a validated machine-learning model. RESULTS: This study included 80 participants: 40 healthy controls and 40 patients with chronic migraine. Evoked somatosensory oscillations were dominant in the alpha band. Longer latency (nonpainful and repetitive painful) and augmented power (nonpainful and repetitive painful) were present among patients with chronic migraine. However, for painful tasks, alpha increases were observed among healthy controls. The oscillatory activity ratios between repetitive painful and painful tasks represented the frequency modulation and power habituation among healthy controls, respectively, but not among patients with chronic migraine. The classification models with oscillatory features exhibited high performance in differentiating patients with chronic migraine from healthy controls. CONCLUSION: Altered oscillatory characteristics of sensory processing and cortical modulation reflected the neuropathology of patients with chronic migraine. These characteristics can be reliably used to identify patients with chronic migraine using a machine-learning approach.

Association of periodontal disease with migraine: A large-scale community-based cross-sectional study.

BACKGROUND: Periodontal disease may drive a systemic inflammatory response that triggers migraine; however, the association between periodontal disease and migraine has rarely been investigated in a community-based setting. METHODS: This cross-sectional study included 66,109 participants aged 30 to 70 years from Taiwan Biobank (TWB). A structured questionnaire was administered to participants, who were also subjected to whole-genome single nucleotide polymorphism genotyping using the customized Axiom-TWB array. To identify subjects with periodontal disease and migraine, the computerized linkage of data obtained from TWB and the National Health Insurance Research Database was performed. Participants were evaluated for their genetic predisposition to migraine using a polygenic risk score. We examined and estimated the magnitude of associations between periodontal disease and migraine. RESULTS: In this study, 4618 (4618/66,109; 7%) participants with migraine and 61,491 (61,491/66,109; 83%) participants without migraine were included. Participants with migraine exhibited a higher prevalence of periodontal disease than participants without migraine (4324/4618; 94% vs. 56,036/61,491; 91%). A significant positive association was observed between periodontal disease and migraine, with an adjusted odds ratio (ORadj ) of 1.40 (95% confidence interval [CI] = 1.24-1.59; p < 0.001). The association remained consistent even after excluding participants with other comorbidities (ORadj  = 1.34; 95% CI = 1.16-1.55; p < 0.001). Moreover, the positive association between periodontal disease and migraine remained significant across the subgroups of age, sex, other comorbidities, and classified polygenic risk scores of migraine, with the ORadj ranging from 1.26 to 1.78. CONCLUSIONS: A significant positive association was observed between periodontal disease and migraine. Future studies need to explore the biological mechanisms of how periodontal disease might affect migraine.

Transient visual disturbances are associated with disability and suicide risk in patients with migraine without aura.

BACKGROUND: To investigate the characteristics and clinical correlates of transient visual disturbances (TVDs) in patients with migraine without aura (MO). Patients with MO frequently report TVDs, which differ from typical visual aura, but the clinical significance of these TVDs has not been determined. METHODS: Patients with MO who attended our headache clinics were enrolled. Structured questionnaires were used to acquire data on participants' headache profiles, disability, comorbidities, and lifetime suicidal ideation and suicide attempts. A semistructured visual phenomenon questionnaire was used to characterize TVDs. Headache specialists interviewed the participants for diagnosis and the verification of questionnaire responses. RESULTS: Patients with MO (n = 7200; female/male ratio = 3.56, mean age 40.1 ± 13.4 years) were divided into two groups based on the presence (n = 2488) or absence (n = 4712) of TVDs. Patients with TVDs had more headache-related disability, psychiatric comorbidities, and photophobia than did those without TVDs. Suicidal ideation and suicide attempts were more common among patients with than among those without TVDs [ideation: odds ratio (OR) = 1.92, 95% confidence interval (CI) 1.71-2.15, p < 0.001; suicide attempt: OR = 2.23, 95% CI 1.80-2.75, p < 0.001]. CONCLUSION: The presence of TVDs may imply greater migraine-related disability, photophobia, and suicidal ideation/suicide attempt risk in patients with MO.

The SIH-EBP Score: A grading scale to predict the response to the first epidural blood patch in spontaneous intracranial hypotension.

BACKGROUND: To develop and validate an easy-to-use scoring system to predict the response to the first epidural blood patching in patients with spontaneous intracranial hypotension. METHODS: This study recruited consecutive patients with spontaneous intracranial hypotension receiving epidural blood patching in a tertiary medical center, which were chronologically divided into a derivation cohort and a validation cohort. In the derivation cohort, factors associated with the first epidural blood patching response were identified by using multivariable logistic regression modeling. A scoring system was developed, and the cutoff score was determined by using the receiver operating characteristic curve. The findings were verified in an independent validation cohort. RESULTS: The study involved 280 patients in the derivation cohort and 78 patients in the validation cohort. The spontaneous intracranial hypotension-epidural blood patching score (range 0-5) included two clinical variables (sex and age) and two radiological variables (midbrain-pons angle and anterior epidural cerebrospinal fluid collections). A score of ≥3 was predictive of the first epidural blood patching response, which was consistent in the validation cohort. Overall, patients who scored ≥3 were more likely to respond to the first epidural blood patching (odds ratio = 10.3). CONCLUSION: For patients with spontaneous intracranial hypotension-epidural blood patching score ≥3, it is prudent to attempt at least one targeted epidural blood patching before considering more invasive interventions.

Clinical Utility of Leeds Dependence Questionnaire in Medication-Overuse Headache.

Dependence behaviors are common in patients with medication-overuse headache (MOH). This prospective study aimed to characterize dependence behaviors in MOH by using Leeds dependence questionnaire (LDQ), and to determine the clinical utility of LDQ in the diagnosis of MOH. In total, 563 consecutive chronic migraine (CM) patients (451F/112M, mean age 41.7 ± 12.0 years) were recruited, including 320 with MOH (56.8%) (254F/66M, mean age 42.3 ± 11.6 years). LDQ scores were positively correlated with the monthly frequency of acute medication use (Spearman's rho = 0.680, p < 0.001). When compared with patients without, those with MOH scored higher on LDQ (13.0 ± 7.6 vs. 3.9 ± 5.1, p < 0.001). By using a receiver operating characteristics curve, the cutoff value of LDQ was determined at 7 (sensitivity = 77.5%, specificity = 77.4%, area under curve = 0.85) for a diagnosis of MOH. An LDQ score of ≥7 was predictive of MOH (odds ratio = 11.80, 95% confidence interval = 7.87-17.67, p < 0.001). In conclusion, the presence of MOH in patients with CM is associated with more severe dependence behaviors. An LDQ score of ≥7 is useful in the detection of MOH in CM patients.

Sphenopalatine ganglion volumetry in episodic cluster headache: from symptom laterality to cranial autonomic symptoms.

BACKGROUND: Sphenopalatine ganglion (SPG) is a peripheral structure that plays an important role in cluster headache (CH). Hence, a reliable method to measure the volume of SPG is crucial for studying the peripheral mechanism of CH. Additionally, the association between the clinical profiles and the morphology of the SPG in CH remains undetermined. This study aims to use the manual measurement of SPG volume to investigate its associations with CH, including headache laterality, cranial autonomic symptoms (CASs), presence of restlessness or agitation, and other clinical profiles. METHODS: We prospectively recruited consecutive CH patients at a tertiary medical center between April 2020 and April 2022. A total of eighty side-locked, in-bout, episodic CH patients and 40 non-headache healthy controls received 1.5 T brain MRI focusing on structural neuroimaging of the SPG. The manual measurement process for SPG was under axial and sagittal FIESTA imaging, with reference T2 weight images (sagittal and axial) for localization. The inter-observer agreement of the SPG volume (both sides of the SPG from CH patients and controls) between the two observers was calculated. In CH patients, clinical profiles and the number of CASs (range 0-5) were recorded to analyze their association with SPG volume. RESULTS: The inter-observer agreement between the two raters was excellent for the new SPG volumetry method at 0.88 (95% CI: 0.84-0.90, p < 0.001). The mean [SD] SPG volume was larger in CH patients than in non-headache controls (35.89 [12.94] vs. 26.13 [8.62] µL, p < 0.001). In CH patients, the SPG volume was larger on the pain side than on the non-pain side (38.87 [14.71] vs. 32.91 [12.70] µL, p < 0.001). The number of CASs was positively moderately correlated with the pain-side SPG volume (Pearson r = 0.320, p = 0.004) but not the non-pain side SPG volume (Pearson r = 0.207, p = 0.066). CONCLUSIONS: This proof-of-concept study successfully measured the SPG volume and demonstrated its associations with symptomatology in patients with episodic CH. The direct measurement of SPG provide insights into studies on peripheral mechanism of CH.