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.

Advancing Li-ion capacitors through dual wet chemical prelithiation.

Lithium-ion batteries (LIBs) and electrical double-layer capacitors (EDLCs) are widely used in commercial energy storage systems, but each has inherent limitations. To overcome these limitations, the lithium-ion capacitor (LIC) has emerged as a hybrid energy storage device, combining the benefits of LIBs and EDLCs. However, the introduction of active lithium into LICs poses challenges due to lithium's reactivity and instability. In this study, we propose a dual wet chemical prelithiation strategy to enhance LIC performance. By wet chemically prelithiating both the activated carbon cathodes and hard carbon anodes, significant improvements are achieved compared to traditional prelithiation methods. The dual prelithiation approach outperforms electrochemical prelithiation in terms of energy storage performance, cycle life, and process simplification. LICs with dual wet chemically prelithiated electrodes demonstrate the highest energy density and retain a substantial portion of reversible capacity even at high discharge rates. The strategy exhibits fast kinetics and wide operational stability. In contrast, LICs with metallic lithium anodes or electrochemically prelithiated hard carbon anodes exhibit inferior performance and limited cycle life. The dual wet chemical prelithiation strategy represents a breakthrough in LIC technology, offering superior performance, cycle stability, and scalability. It holds promise for alkali-ion energy storage systems and drives advancements in electrochemical energy storage technology.

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 cerebral interstitial fluid dynamics in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, caused by cysteine-altering variants in NOTCH3, is the most prevalent inherited cerebral small vessel disease. Impaired cerebral interstitial fluid dynamics has been proposed as one of the potential culprits of neurodegeneration and may play a critical role in the initiation and progression of cerebral small vessel disease. In the present study, we aimed to explore the cerebral interstitial fluid dynamics in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy and to evaluate its association with clinical features, imaging biomarkers and disease severity of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. Eighty-one participants carrying a cysteine-altering variant in NOTCH3, including 44 symptomatic cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy patients and 37 preclinical carriers, and 21 age- and sex-matched healthy control individuals were recruited. All participants underwent brain MRI studies and neuropsychological evaluations. Cerebral interstitial fluid dynamics was investigated by using the non-invasive diffusion tensor image analysis along the perivascular space method. We found that cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy patients exhibited significantly lower values of diffusion tensor image analysis along the perivascular space index comparing to preclinical carriers and healthy controls. For the 81 subjects carrying NOTCH3 variants, older age and presence of hypertension were independently associated with decreased diffusion tensor image analysis along the perivascular space index. The degree of cerebral interstitial fluid dynamics was strongly related to the severity of cerebral small vessel disease imaging markers, with a positive correlation between diffusion tensor image analysis along the perivascular space index and brain parenchymal fraction and negative correlations between diffusion tensor image analysis along the perivascular space index and total volume of white matter hyperintensity, peak width of skeletonized mean diffusivity, lacune numbers and cerebral microbleed counts. In addition, diffusion tensor image analysis along the perivascular space index was a significant risk factor associated with the development of clinical symptoms of stroke or cognitive dysfunction in individuals carrying NOTCH3 variants. In cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy patients, diffusion tensor image analysis along the perivascular space index was significantly associated with Mini-Mental State Examination scores. Mediation analysis showed that compromised cerebral interstitial fluid dynamics was not only directly associated with cognitive dysfunction but also had an indirect effect on cognition by influencing brain atrophy, white matter disruption, lacunar lesions and cerebral microbleeds. In conclusion, cerebral interstitial fluid dynamics is impaired in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy and its disruption may play an important role in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. Diffusion tensor image analysis along the perivascular space index may serve as a biomarker of disease severity for cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy.

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.

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.

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.

Atezolizumab-induced subacute cerebellar ataxia in a patient with extensive-stage small cell lung cancer.

Recently, immune checkpoint inhibitors (ICIs) have become the standard treatment option for patients with lung cancer, including small cell lung cancer (SCLC). ICI-induced neurological immune-related adverse events are rare and exhibit diverse clinical manifestations, often leading to missed or delayed diagnosis. Herein, we report the case of a patient with extensive-stage SCLC who received atezolizumab with etoposide/platinum and gradually developed neurological symptoms after three cycles of chemoimmunotherapy. Subsequently, the patient received a diagnosis of subacute immune-related cerebellar ataxia and was treated successfully with pulse steroid therapy. The patient exhibited almost complete remission of neurological symptoms and had progression-free survival for >24 months.

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 m.3243A>G mitochondrial DNA mutation in patients with cerebellar ataxia.

BACKGROUND: The mitochondrial DNA m.3243A>G mutation can affect mitochondrial function and lead to a wide phenotypic spectrum, including mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, diabetes mellitus, hearing impairment, cardiac involvement, epilepsy, migraine, myopathy, and cerebellar ataxia. However, m.3243A>G has been rarely reported in patients with cerebellar ataxia as their predominant manifestation. The aim of this study is to investigate the prevalence and clinical features of m.3243A>G in a Taiwanese cohort of cerebellar ataxia with unknown genetic diagnosis. METHODS: This retrospective cohort study conducted the mutation analysis of m.3243A>G by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) in 232 unrelated Han Chinese patients with genetically-undetermined cerebellar ataxia. The clinical presentation and neuroimaging features of patients with m.3243A>G mutation-related cerebellar ataxia were characterized. RESULTS: We identified two patients harboring m.3243A>G mutation. These patients have suffered from apparently sporadic and slowly progressive cerebellar ataxia since age 52 and 35 years, respectively. Both patients had diabetes mellitus and/or hearing impairment. The neuroimaging studies revealed generalized brain atrophy with predominantly cerebellar involvement in both individuals and bilateral basal ganglia calcifications in one of the patients. CONCLUSION: Mitochondrial m.3243A>G mutation accounted for 0.9% (2/232) of genetically-undetermined cerebellar ataxia in the Han Chinese cohort in Taiwan. These findings highlight the importance of investigating m.3243A>G in patients with genetically-undetermined cerebellar ataxia.

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.

An altered reward system characterizes chronic migraine with medication overuse headache.

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.

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.

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.

Reduced-penetrance Huntington's disease-causing alleles with 39 CAG trinucleotide repeats could be a genetic factor of amyotrophic lateral sclerosis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: The HTT allele with 39 CAG repeats could be a genetic factor linked to ALS susceptibility.

Clinical and genetic characterization of NEFL-related neuropathy in Taiwan.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Brain morphometry changes with fatigue severity in fibromyalgia.

OBJECTIVES: This study investigated brain morphometry changes associated with fatigue severity in fibromyalgia (FM). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Resting-state magnetoencephalographic oscillatory connectivity to identify patients with chronic migraine using machine learning.

To identify and validate the neural signatures of resting-state oscillatory connectivity for chronic migraine (CM), we used machine learning techniques to classify patients with CM from healthy controls (HC) and patients with other pain disorders. The cross-sectional study obtained resting-state magnetoencephalographic data from 240 participants (70 HC, 100 CM, 35 episodic migraine [EM], and 35 fibromyalgia [FM]). Source-based oscillatory connectivity of relevant cortical regions was calculated to determine intrinsic connectivity at 1-40 Hz. A classification model that employed a support vector machine was developed using the magnetoencephalographic data to assess the reliability and generalizability of CM identification. In the findings, the discriminative features that differentiate CM from HC were principally observed from the functional interactions between salience, sensorimotor, and part of the default mode networks. The classification model with these features exhibited excellent performance in distinguishing patients with CM from HC (accuracy ≥ 86.8%, area under the curve (AUC) ≥ 0.9) and from those with EM (accuracy: 94.5%, AUC: 0.96). The model also achieved high performance (accuracy: 89.1%, AUC: 0.91) in classifying CM from other pain disorders (FM in this study). These resting-state magnetoencephalographic electrophysiological features yield oscillatory connectivity to identify patients with CM from those with a different type of migraine and pain disorder, with adequate reliability and generalizability.

Non-aura visual disturbance with high visual aura rating scale scores has stronger association with migraine chronification than typical aura.

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 < 0.001). The associations remained after adjusting confounding factors. 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.