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Background 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. Methods 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. Results 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 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. Conclusions 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).

Background The role of the NOTCH3 p.R544C variant, the predominant variant of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in multiple East Asian regions, in migraine is unknown. Methods Migraine patients (n = 2,884) (2,279F/605M, mean age 38.8 ± 11.7 years), including 324 (11.2%) with migraine with aura, were prospectively enrolled by headache specialists according to the International Classification of Headache Disorders criteria. These patients and 3,502 population controls free of stroke, dementia, and headache were genotyped for NOTCH3 p.R544C by TaqMan genotyping assay or Axiom Genome-Wide TWB 2.0 Array. Clinical manifestations and brain magnetic resonance images were examined and compared between migraine patients with and without NOTCH3 p.R544C. Results Thirty-two migraine patients (1.1%) and 36 controls (1.0%) harbored the p.R544C variant, and the percentages were comparable among migraine patients without and with aura, and controls (1.2%, vs. 0.6% vs. 1.0%, p = 0.625). Overall, migraine patients with and without the p.R544C variant had similar percentages of migraine with aura, headache characteristics, frequencies and disabilities. However, those with p.R544C were less likely to have pulsatile headaches (50.0% vs. 68.2%, p = 0.028), and more likely to have moderate to severe white matter hyperintensities in the external capsule (18.8% vs. 1.2%, p = 0.006) and anterior temporal lobe (12.5% vs. 0%, p = 0.008). Conclusions Our findings suggest that NOTCH3 p.R544C does not increase the risk of migraine with aura, or migraine as a whole, and generally does not alter clinical manifestations of migraine. The role of NOTCH3 variants, as well as potential influences from ethnicity or modifier genes, in migraine needs to be further clarified.

Expanded HTT alleles with 40 or more CAG repeats were recently found to be a rare cause of frontotemporal dementia and amyotrophic lateral sclerosis (ALS) spectrum diseases. The aim of this study was to investigate the role of HTT repeat expansions in a Taiwanese cohort with ALS.We analyzed the numbers of CAG repeats in exon 1 of HTT in a cohort of 410 Taiwanese patients with ALS and 1514 control individuals by utilizing polymerase chain reaction and amplicon fragment length analysis.Only one of the 410 ALS patients carried a reduced-penetrance HD-causing allele with 39 CAG repeats, and none had an expanded HTT CAG repeats ≥40. The patient presented with rapidly progressive bulbar-onset ALS with disease onset at the age of 64 years. He had neither chorea nor cognitive impairment. He had a family history of chorea, but no other family member manifested with ALS. None of the 1514 control individuals carried an HTT expanded allele with CAG repeats larger than 37 repeats.The HTT allele with 39 CAG repeats could be a genetic factor linked to ALS susceptibility.

Objective Mutations in the colony‐stimulating factor 1 receptor gene (CSF1R) were identified as a cause of adult‐onset inherited leukoencephalopathy. The present study aims at investigating the frequency, clinical characteristics, and functional effects of CSF1R mutations in Taiwanese patients with adult‐onset leukoencephalopathy. Methods Mutational analysis of CSF1R was performed in 149 unrelated individuals with leukoencephalopathy by a targeted resequencing panel covering the entire coding regions of CSF1R. In vitro analysis of the CSF1‐induced autophosphorylation activities of mutant CSF1R proteins was conducted to assess the pathogenicity of the CSF1R mutations. Results Among the eight CSF1R variants identified in this study, five mutations led to a loss of CSF1‐induced autophosphorylation of CSF1R proteins. Four mutations (p.K586*, p.G589R, p.R777Q, and p.R782C) located within the tyrosine kinase domain of CSF1R, whereas the p.T79M mutation resided in the immunoglobulin‐like domain. The five patients carrying the CSF1R mutations developed cognitive decline at age 41, 43, 50, 79, and 86 years, respectively. Psychiatric symptoms and behavior changes were observed in four of the five patients. The executive function and processing speed were severely impaired at an early stage, and their cognitive function deteriorated rapidly within 3–4 years. Diffusion‐restricted lesions at the subcortical regions and bilateral corticospinal tracts were found in three patients. Interpretation CSF1R mutations account for 3.5% (5/149) of the adult‐onset leukoencephalopathy in Taiwan. CSF1R mutations outside the tyrosine kinase domain may also disturb the CSF1R function and lead to the clinical phenotype. Molecular functional validation is important to determine the pathogenicity of novel CSF1R variants.

Preventive treatment is crucial for patients with chronic migraine (CM). This study explored the association between resting-state cortical oscillations and 3-month treatment outcome in patients with CM. Treatment-naïve patients with CM were recruited with their demographic data, psychosocial data, and headache profiles as well as the healthy controls (HCs). Resting-state cortical activities were recorded using an electroencephalogram and analysed using source-based and electrode-based spectral power method. The regions of interest were the bilateral primary somatosensory (S1) and visual (V1) cortices. After 3-month treatment with flunarizine, patients with CM were categorized into responders and nonresponders. Demographic, clinical, and electroencephalogram data from 72 patients with CM and 50 HCs were analysed. Elevated anxiety, depression, and stress were observed in patients with CM. Theta power in bilateral S1 and alpha and gamma powers in the right S1 increased in patients with CM. Nonresponders (n = 34) exhibited larger alpha powers in bilateral V1 than those in responders (n = 38). Alpha powers also exhibited significant correlations with changes of monthly headache days. Notably, in responders and nonresponders, occipital alpha powers did not differ at baseline and in the third month. In conclusion, patients with CM who were not responsive to preventive treatment were associated with augmented resting-state occipital alpha activity. Moreover, changes in migraine attack frequency were associated with baseline occipital alpha power. However, the prognostic feature of visual alpha oscillation seems to be inherent because it is not altered by flunarizine treatment. These findings may be useful for developing personalised migraine treatment plans.

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 p p 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.

Objectives To investigate the clinical correlates of visual symptoms in patients with migraine. Method Patients with migraine that attended our headache clinics were enrolled. Headache profiles, disability, and comorbidities were acquired with structured questionnaires. A semi-structured visual phenomenon questionnaire was also used to assess the characteristics of visual symptoms, including visual aura in patients with migraine with aura and transient visual disturbance in patients with migraine without aura. Headache specialists interviewed with the participants for the ascertainment of diagnosis and verification of the questionnaires. Result Migraine with aura patients with visual aura (n = 743, female/male = 2.3, mean age: 34.7 ± 12.2 years) and migraine without aura patients with non-aura transient visual disturbance (n = 1,808, female/male = 4.4, mean age: 39.4 ± 12.6 years) were enrolled. Patients with transient visual disturbance had higher headache-related disability and more psychiatric comorbidities. Chronic migraine was more common in migraine without aura than migraine with aura patients (41.9% vs. 11.8%, OR = 5.48 [95% CI: 4.33–7.02], p Conclusion Presence of non-aura transient visual disturbance may suggest a higher migraine-related disability and is linked to higher risk of chronic migraine than typical migraine aura in migraine patients. Further studies are needed to elucidate the potential mechanism.

Objectives To compare the clinical profiles between male and female cluster headache patients from a large cohort. Methods This hospital-based study enrolled patients diagnosed with cluster headache between 1997 to 2021. Participants completed structured questionnaires collecting information on demographics, clinical profiles, and quality of life. Treatment regimens and effectiveness were determined through medical chart review. All variables were compared between the sexes. Results In total, 798 patients (M/F:659/139) were enrolled. The male-to-female ratio was 4.7:1 for the full study period, but it declined from 5.2:1 to 4.3:1 for patients enrolled before and after 2010, respectively. The frequencies of chronic cluster headache (M:1.2%, F:1.4%) and aura (M:0.3%, F:0.7%) were low but similar between the sexes. Most headache features showed no difference between men and women. Female patients had significantly longer attack duration, shorter inter-bout duration, higher frequencies for eyelid edema, nausea and vomiting and lower frequencies for conjunctival injection and pacing. Sex difference did not influence headache-associated disability, anxiety, or depression, but poor sleep quality was significantly more common in women. Among menstruating women, 22/122 (18.0%) reported worsening headaches during menses. The effectiveness of treatment was similar between the sexes. Conclusions Despite a decline of male-to-female ratio in the past two decades, most clinical profiles were similar between the sexes.

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.

This study investigated brain morphometry changes associated with fatigue severity in fibromyalgia (FM).Clinical profiles and brain-MRI data were collected in patients with FM. Patients were divided into three groups based on their fatigue severity. Using voxel-based morphometry analysis and trend analysis, neural substrates showing volumetric changes associated with fatigue severity across the three groups were identified. Their seed-to-voxel structural covariance (SC) networks with the whole brain were studied in distribution and strength.Among the 138 enrolled patients with FM, 23, 57, and 58 were categorised into the mild, moderate, and severe fatigue groups, respectively. The number of musculoskeletal pain regions and intensity of pain were not associated with fatigue severity, but somatic symptoms and psychiatric distress, including waking unrefreshed, depression, and anxiety, were associated with fatigue severity. After adjusting for anxiety and depression, decreased bilateral thalamic volumes were associated with higher fatigue severity. The SC distributions of the thalamic seed were more widespread to the frontal, parietal, subcortical, and limbic regions in patients with higher fatigue severity. In addition, increased right inferior temporal cortex volumes were associated with higher fatigue severity. The SC distributions of the right inferior temporal seed were more over the temporal cortex and the SC strengths of the seed were higher with the bilateral occipital cortex in patients with higher fatigue severity.The thalamus and the right inferior temporal cortex are implicated in the manifestation of fatigue severity in FM. Future therapeutic strategies targeting these regions are worthy of investigation.

Background Previous voxel- or surface-based morphometric analysis studies have revealed alterations in cortical structure in patients with chronic migraine, yet with inconsistent results. The discrepancies may be derived partly from the sample heterogeneity. Employing both methods in a clinically homogenous group may provide a clearer view. Methods Structural MRI data from 30 prevention-naïve patients with chronic migraine without medication overuse headache or a history of major depression and 30 healthy controls were analyzed. Vertex-wise (surface-based) or voxel-wise (voxel-based) linear models were applied, after controlling for age and gender, to investigate between-group differences. Averaged cortical thicknesses and volumes from regions showing group differences were correlated with parameters related to clinical profiles. Results Surface-based morphometry showed significantly thinner cortices in the bilateral insular cortex, caudal middle frontal gyrus, precentral gyrus, and parietal lobes in patients with chronic migraine relative to healthy controls. Additionally, the number of migraine days in the month preceding MRI examination was correlated negatively with right insular cortical thickness. Voxel-based morphometry (VBM) did not show any group differences or clinical correlations. Conclusion Patients with chronic migraine without medication overuse headache, major depression, or prior preventive treatment had reduced cortical thickness in regions within the pain-processing network. Compared to voxel-based morphometry, surface-based morphometry analysis may be more sensitive to subtle structural differences between healthy controls and patients with chronic migraine.

Background The increase of headache frequency is associated with higher headache related disability and lower quality of life in patients with migraine. However, the pathophysiology of migraine progression, persistence, or remission is elusive. The purpose of this study is to identify the brain signatures that are predictive of the long-term outcomes among patients with high-frequency migraine (HFM: 10–30 headache days/month). Methods We prospectively enrolled patients with HFM and healthy controls and collected their baseline clinical profiles and brain-MRI data at first visit. We longitudinally followed the patients and determined their outcomes at 2-year follow-up. Good outcome was defined as ≥50% reduction of baseline headache days and poor outcome was defined as reduction Results Among 56 patients with HFM, 37 had good outcome and 19 poor outcome. Compared to the healthy controls (n = 37), patients with poor outcome had decreased GMV over the left posterior cingulate gyrus, and increased GMV over the bilateral cerebellum and the right precentral gyrus. Further, patients with poor outcome had greater GMV over the right and the left cerebella compared to patients with good outcome, and the GMVs of the cerebella were correlated to 2-year headache frequencies (right: r = 0.38, P = 0.005; left: r = 0.35, P = 0.009). Structural connectivity were increased between the cerebellum and the cuneus, the calcarine cortex, and the temporal lobe, respectively, in patients with poor outcome, and was decreased between the cerebellum and the prefrontal cortex in patients with poor outcome. The structural covariance integrities between the right cerebellum and the right cuneus were correlated to 2-year headache frequencies (r = 0.36, P = 0.008). Conclusions Structural volume and connectivity changes of the cerebellum may underlie headache persistence in patients with HFM.

Mutations in the neurofilament light polypeptide gene (NEFL) are an uncommon cause of Charcot-Marie-Tooth disease (CMT). The aim of this study is to elucidate the clinical characteristics and genetic spectrum of NEFL-related neuropathy in a Taiwanese CMT cohort.Mutational analysis of the coding regions of NEFL was performed by Sanger sequencing or targeted resequencing. Twenty-one patients from nine CMT pedigrees, identified from a cohort of 508 unrelated CMT patients, were found to have a NEFL mutation. Genetic, clinical and electrophysiological features were analyzed.Six NEFL mutations were identified, including two novel ones (p.P8S, p.N98Y). NEFL p.E396K was the most common mutation, accounting for 33.3% of the patients in our cohort. All patients manifested sensorimotor polyneuropathy with a mean age of disease onset of 13.5 ± 9.6 (1-40) years. Their motor nerve conduction velocities (MNCVs) of the ulnar nerve ranged from 22.1 to 48.7 m/s. Seventy percent of the patients could be classified as intermediate CMT with ulnar MNCVs between 25 and 45 m/s. Six of the 21 patients (28.6%) had additional features of central nervous system (CNS) involvement, including motor developmental delay, spasticity, cerebellar signs, neuropathic pain and scoliosis.NEFL mutations account for 1.8% (9/508) of the CMT patients in Taiwan. The present study delineates the clinical and genetic characteristics of NEFL-related neuropathy in Taiwan, and highlights that ulnar MNCV above 25 m/s and CNS involvement may serve as diagnostic clues for NEFL-related neuropathy.

Background: Patients with migraine without aura frequently report transient visual disturbances (TVD) other than typical visual aura, but the clinical correlates are not determined. Method: Patients with migraine without aura (MO) that attended the headache clinic were enrolled. Structured questionnaires were self-administered by the patients including headache profiles, comorbidities, lifetime suicidal ideation and attempts, six-item Headache Impact Test, Migraine Photophobia Score, Migraine Disability Assessment, Hospital Anxiety and Depression Scale, Beck Depression Inventory, and Pittsburgh Sleep Quality Index. A semi-structured visual phenomenon questionnaire was also used to assess the characteristics of TVDs. TVD is defined as any zigzag flashes, flickering dots/lines, or blurred/foggy vision associated with headache and with a Visual Aura Rating Scale < 4. Headache specialists interviewed with the participants for the ascertainment of diagnosis and verified of the questionnaires.Result: MO patients (n = 7,200, female/male = 3.56, mean age: 40.1 ± 13.4 years) were divided into 2 subgroups based on the presence (n=2,488) or absence of TVDs (n= 4,712). Patients with TVD had higher headache-related disability, more psychiatric comorbidities and were more likely to be photophobic. Suicidal ideation and attempts were more common in patients with TVD than in those without (ideation: 31.9% vs. 18.1%, OR = 1.92 [95% CI: 1.71−2.15], p < 0.001; attempt: 8.2% vs. 3.5%, OR = 2.23 [95% CI: 1.80−2.75], p < 0.001). The associations remained after adjustment of confounding factors.Conclusion: Presence of transient visual disturbance may suggest a higher migraine-related disability, higher level of photophobia and higher suicidal ideation/attempts in MO patients.

Many patients with fibromyalgia (FM) experience fatigue, but the associated biological mechanisms have not been delineated. We aimed to investigate the neural signatures associated with fatigue severity in patients with FM using MRI. We consecutively recruited 138 patients with FM and collected their clinical profiles and brain-MRI data. We categorized the patients into 3 groups based on their fatigue severity. Using voxel-based morphometry analysis and trend analysis, we first identified neural structures showing volumetric changes associated with fatigue severity, and further explored their seed-to-voxel structural covariance networks (SCNs). Results showed decreased bilateral thalamic volumes were associated with higher severity of fatigue. There was a more widespread distribution of the thalamic SCNs to the frontal, parietal, subcortical, and limbic regions in patients with higher fatigue severity. In addition, increased right inferior temporal cortex volumes were associated with higher severity of fatigue. The right inferior temporal seed showed more SCNs distributions over the temporal cortex and a higher strength of SCNs to the bilateral occipital cortex in patients with higher fatigue severity. The thalamus and the right inferior temporal cortex as well as their altered interactions with cortical and subcortical regions comprise the neural signatures of fatigue in FM.

Background Medication overuse headache shares several characteristics with substance use disorders. However, key features of substance use disorders such as increased impulsivity and alterations in reward processing remain little explored in medication overuse headache. Methods Temporal discounting and impulsive decision making behavior and the associated brain mechanisms were assessed in 26 chronic migraine patients with medication overuse headache and in 28 healthy controls. Regions-of-interest analyses were first performed for task-related regions, namely the ventral striatum and the ventromedial and dorsomedial prefrontal cortices. Resting-state functional connectivity between these regions were then explored. An additional 27 chronic migraine patients without medication overuse headache were included for comparison in the latter analysis. Results Patients with medication overuse headache showed steeper temporal discounting behavior than healthy controls. They also showed weaker subjective value representations in the dorsomedial prefrontal cortex, when accepting larger delayed rewards, and in ventral striatum and ventromedial prefrontal cortex, when accepting the smaller immediate reward. Resting-state functional connectivity was reduced among the valuation regions when comparing patients with medication overuse headache to the other two control groups. Conclusions Patients with medication overuse headache were characterized by altered processing and dysconnectivity in the reward system during intertemporal choices and in the resting-state.

ObjectivesTo identify the neuroimaging predictors for the responsiveness of patients to sumatriptan and use an independent cohort for external validation.MethodsStructuralized headache questionnaire and 3-Tesla brain magnetic resonance imaging were performed in migraine patients. Regional brain volumes were automatically calculated using FreeSurfer version 6.0, including bilateral amygdala, anterior cingulated cortex, caudate, putamen, precuneus, orbitofrontal cortex, superior frontal gyri, middle frontal gyri, hippocampus, and parahippocampus. A sumatriptan-responder was defined as headache relief within 2 h after the intake of sumatriptan in at least two out of three treated attacks. We constructed a prediction model for sumatriptan response using the regional brain volume and validated it with an independent cohort of migraine patients.ResultsA total of 105 migraine patients were recruited, including 73 sumatriptan responders (69.5%) and 32 (30.5%) non-responders. We divided the migraine patients into derivation (n = 73) and validation cohorts (n = 32). In the derivation cohort, left hippocampal volume was larger in sumatriptan responders (responders vs. non-responders: 3,929.5 ± 403.1 vs. 3,611.0 ± 389.9 mm3, p = 0.002), and patients with a larger left hippocampal volume had a higher response rate to sumatriptan (>4,036.2 vs. ≤4,036.2 mm3: 92.0 vs. 56.3%, p = 0.001). Based on the findings, we constructed a prediction model using the cutoff value of 4,036.2 mm3, and we found that patients with a left hippocampal volume >4,032.6 mm3 had a higher response rate to sumatriptan than those with a left hippocampal volume ≤4,032.6 mm3 (84.6 vs. 42.1%, odds ratio [OR] = 7.6 [95% confidence interval = 1.3–44.0], p = 0.013) in the validation cohort.ConclusionOur study showed that left hippocampal volume is helpful to identify sumatriptan non-responders. This proof-of-concept study shows that left hippocampal volume could be used to predict the treatment response to sumatriptan in migraine patients.

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

To investigate the distribution, clinical associations, and treatment responses for the most bothersome symptoms of migraine in a large sample of patients with migraine in Taiwan.The most bothersome symptom is recently recommended as a co-primary endpoint in clinical trials of acute treatment of migraine. However, most clinical trials and observational studies have been conducted in the United States and Europe, with photophobia representing the most common most bothersome symptom.Patients who were newly diagnosed with migraine by headache specialists in Taipei Veterans General Hospital were recruited. All participants completed a questionnaire for headache profile, including the most bothersome symptom. Clinical associations of the most bothersome symptoms and response rates to previous acute treatments were analyzed.Among the recruited 1188 patients with migraine (female 79.4%, mean age 39.0 ± 12.1 years) in this cross-sectional study, nausea (n = 729/1188, 61.4%) was the most common symptom that was most bothersome, followed by phonophobia (n = 280/1188, 23.6%), and photophobia (n = 122/1188, 10.3%). The frequency ranking was the same regardless of sex and age. Compared to migraine without aura, migraine with aura was associated with photophobia (adjusted odds ratio [OR] = 2.97, 95% confidence interval [CI] 1.76-5.0, p 0.001). Chronic migraine was associated with phonophobia (adjusted OR = 1.51, 95% CI 1.13-2.01, p = 0.005), but there was a lower chance for nausea (adjusted OR = 0.68, 95% CI 0.53-0.88, p = 0.004), as the most bothersome symptom. Patients with different most-bothersome symptoms responded similarly to previous acute treatments, with an overall response rate of 52.2% (n = 550/1053).Patients with migraine in Taiwan reported a distinct ranking of the most bothersome symptom. However, the response rates of the most bothersome symptom and headache were similar, which supports the most bothersome symptom as an outcome measure for acute treatment of migraine. Further studies recruiting different populations are required to investigate regional differences in most bothersome symptoms.

Despite diffuse tenderness, patients with fibromyalgia (FM) have reported a wide range of areas with musculoskeletal pain. This study investigated the neural structures and neuroanatomical networks associated with self-reported widespread pain in FM using magnetic resonance imaging. We collected clinical profiles and brain magnetic resonance imaging data of newly diagnosed patients with FM. A total of 138 patients with FM were divided into 3 subgroups based on the number of pain areas, with 3 to 8, 9 to 12, and 13 to 19 areas, respectively. Using voxel-based morphometry analysis, we first identified the neural structure that showed a trend of volumetric change across the 3 subgroups. We then used it as a candidate seed of interest with a seed-to-voxel analytical approach to explore the structural covariance (SC) networks of the whole brain. Finally, we studied the trend of changes in the distribution and strength of SC networks across subgroups of patients. We found a decreasing trend in the volumes of the right anterior insular cortex (rAIC) across the 3 subgroups that had an increased number of pain areas. An increasing trend in the number of neural substrates over the subcortical regions, especially the basal ganglion, showed SC to the rAIC, and a decreasing trend of SC strength was shown between the rAIC and the precuneus, frontal cortex, anterior and posterior cingulate, and lingual gyri, across the patient subgroups with increased pain areas. The rAIC and its altered connection with specific brain regions indicates widespread pain in patients with FM.