The Prevalence and Clinical Phenotypes of Cluster Headache in Relation with Latitude.

PURPOSE OF REVIEW: Previous studies have indicated a possible link between the prevalence of cluster headache (CH) and sunlight exposure. However, this theory has yet to be tested systemically. In this article, we aim to examine how latitude affects the prevalence and phenotypes of CH. RECENT FINDINGS: To our knowledge, there is by far no article describing the effect of latitude on disease phenotype; thus, we performed a literature review. We noted positive effects of latitude on 1-year prevalence, the proportion of chronic CH, and the proportion of miosis and/or ptosis. Latitude may affect the phenotypic presentations of cluster headache, probably partially mediated via temperature and sunlight variations. Still, other factors, such as environmental exposure to smoking and the genetic difference between the Eastern and Western populations, may participate in the pathogenesis and clinical manifestations of CH.

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.

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.

Cellular mechanisms underlying central sensitization in a mouse model of chronic muscle pain.

Chronic pain disorders are often associated with negative emotions, including anxiety and depression. The central nucleus of the amygdala (CeA) has emerged as an integrative hub for nociceptive and affective components during central pain development. Prior adverse injuries are precipitating factors thought to transform nociceptors into a primed state for chronic pain. However, the cellular basis underlying the primed state and the subsequent development of chronic pain remains unknown. Here, we investigated the cellular and synaptic alterations of the CeA in a mouse model of chronic muscle pain. In these mice, local infusion of pregabalin, a clinically approved drug for fibromyalgia and other chronic pain disorders, into the CeA or chemogenetic inactivation of the somatostatin-expressing CeA (CeA-SST) neurons during the priming phase prevented the chronification of pain. Further, electrophysiological recording revealed that the CeA-SST neurons had increased excitatory synaptic drive and enhanced neuronal excitability in the chronic pain states. Finally, either chemogenetic inactivation of the CeA-SST neurons or pharmacological suppression of the nociceptive afferents from the brainstem to the CeA-SST neurons alleviated chronic pain and anxio-depressive symptoms. These data raise the possibility of targeting treatments to CeA-SST neurons to prevent central pain sensitization.

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.

Clinical characteristics and long-term outcome of cerebral cavernous malformations-related epilepsy.

OBJECTIVE: Cerebral cavernous malformations (CCMs) present variably, and epileptic seizures are the most common symptom. The factors contributing to cavernoma-related epilepsy (CRE) and drug resistance remain inconclusive. The outcomes of CRE after different treatment modalities have not yet been fully addressed. This study aimed to characterize the clinical features of patients with CRE and the long-term seizure outcomes of medical and surgical treatment strategies. METHODS: This was a retrospective cohort of 135 patients with CCM who were diagnosed in 2007-2011 and followed up for 93.6 months on average. The patients were divided into drug-resistant epilepsy (DRE; n = 29), non-DRE (n = 45), and no epilepsy (NE; n = 61). RESULTS: Temporal CCM was the factor most strongly associated with the development of both CRE and DRE. The majority of patients with single temporal CCMs had CRE (86.8%, n = 33), and 50% had DRE, whereas only 14.7% (n = 5) with a nontemporal supratentorial CCM had DRE (p < .05). The most common lesion site in the DRE group was the mesiotemporal lobe (50%). Multiple CCMs were more frequently observed in the CRE (29.2%) than the NE (11.5%) group (p < .05). In patients with CRE, multiple lesions were associated with a higher rebleeding rate (odds ratio = 11.1), particularly in those with DRE (odds ratio = 15.4). The majority of patients who underwent resective surgery for DRE (76.5%, n = 13) achieved International League Against Epilepsy Class I and II seizure outcomes even after a long disease course. SIGNIFICANCE: Temporal CCM not only predisposes to CRE but also is a major risk factor for drug resistance. The mesiotemporal lobe is the most epileptogenic zone. Multiple CCMs are another risk factor for CRE and increase the rebleeding risk in these patients. Surgical resection could provide beneficial long-term seizure outcomes in patients with DRE.

Evaluating Teaching Effectiveness of Medical Humanities in an Integrated Clerkship Program by a Novel Prospective Propensity Score Matching Framework.

BACKGROUND: This study aims to rigorously compare the effectiveness of the educational programs of a new integrated clinical clerkship in medicine (3 months) and surgery (3 months) at a cancer center with the conventional subspecialty-based rotations at a tertiary teaching hospital, by this prospective, pre-post comparative method. METHODS: Between 2013-2016, we compared 69 students who had selected the integrated clerkship that emphasized clinical competency and medical humanities training with 138 matched peers who had completed conventional clerkships during the same period. Outcome measures for medical humanities included empathy, patient-centeredness, and other values and skills related to holistic health care professionalism by introducing prospective propensity score matching (PSM). RESULTS: At baseline, no significant between-group differences existed. At the completion of the core clerkships, students receiving the integrative clerkship had significantly higher scores on the Patient-Practitioner Orientation Scale (PPOS) and the Professionalism Climate in Clinical Teaching Environment (PCI), and similar Jefferson Scale of Physician Empathy Student Version (JSPE) scores, as compared with the comparison group. We also found that the students in this program did not perform worse than those in the traditional internship group in the comprehensive and formative OSCE medical clinical skills test. CONCLUSIONS: Our study develops an empirical basis for rigorous evaluation to design medical education to improve the medical humanities values and skills of interns. Features of the new integrated clerkship program that we developed include substantial participation by the students in patient-centered in-hospital culture, as well as reflection, discussion, and feedback on actual clinical cases.

Right anterior insula is associated with pain generalization in patients with fibromyalgia.

ABSTRACT: 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.

Diagnosis and classification of headache associated with sexual activity using a composite algorithm: A cohort study.

BACKGROUND: To differentiate primary headache associated with sexual activity from other devastating secondary causes. METHODS: In this prospective cohort, we recruited consecutive patients with at least 2 attacks of headache associated with sexual activity from the headache clinics or emergency department of a national medical center from 2005 to 2020. Detailed interview, neurological examination, and serial thorough neuroimaging including brain magnetic resonance imaging and magnetic resonance angiography scans were performed on registration and during follow-ups. Patients were categorized into four groups, i.e. primary headache associated with sexual activity, reversible cerebral vasoconstriction syndrome, probable reversible cerebral vasoconstriction syndrome, and other secondary headache associated with sexual activity through a composite clinic-radiological diagnostic algorithm. We compared the clinical profiles among these groups, including sex, age of onset, duration, quality, and clinical course ("chronic" indicates disease course ≥ 1 year). In addition, we also calculated the score of the reversible cerebral vasoconstriction syndrome2, a scale developed to differentiate reversible cerebral vasoconstriction syndrome from other intracranial vascular disorders. RESULTS: Overall, 245 patients with headache associated with sexual activity were enrolled. Our clinic-radiologic composite algorithm diagnosed and classified all patients into four groups, including 38 (15.5%) with primary headache associated with sexual activity, 174 (71.0%) with reversible cerebral vasoconstriction syndrome, 26 (10.6%) with probable reversible cerebral vasoconstriction syndrome, and 7 (2.9%) with other secondary causes (aneurysmal subarachnoid hemorrhage (n = 4), right internal carotid artery dissection (n = 1), Moyamoya disease (n = 1), and meningioma with hemorrhage (n = 1)). These four groups shared similar clinical profiles, except 26% of the patients with primary headache associated with sexual activity had a 3 times greater chance of running a chronic course (≥ 1 year) than patients with reversible cerebral vasoconstriction syndrome. Of note, the reversible cerebral vasoconstriction syndrome2 score could not differentiate reversible cerebral vasoconstriction syndrome from other groups. CONCLUSION: Our composite clinic-radiological diagnostic algorithm successfully classified repeated headaches associated with sexual activity, which were predominantly secondary and related to vascular disorders, and predicted the prognosis. Primary headache associated with sexual activity and reversible cerebral vasoconstriction syndrome presented with repeated attacks of headache associated with sexual activity may be of the same disease spectrum.

Somatosensory Gating Responses Are Associated with Prognosis in Patients with Migraine.

Sensory gating, a habituation-related but more basic protective mechanism against brain sensory overload, is altered in patients with migraine and linked to headache severity. This study investigated whether somatosensory (SI) gating responses determined 3-months treatment outcomes in patients with episodic migraine (EM) and chronic migraine (CM). A 306-channel magnetoencephalography (MEG) with paired-pulse stimulation paradigm was used to record their neuromagnetic responses. To calculate the peak amplitude and latency and compute the gating ratios (second vs. first amplitude), the first and second responses to the paired stimuli from the primary somatosensory cortex were obtained. All patients were assigned to subgroups labeled good or poor according to their headache frequency at baseline compared with at the third month of treatment. The gating ratio in the CM group (n = 37) was significantly different between those identified as good and poor (p = 0.009). In the EM group (n = 30), the latency in the second response differed by treatment outcomes (p = 0.007). In the receiver operating characteristic analysis, the areas under the curve for the CM and EM groups were 0.737 and 0.761, respectively. Somatosensory gating responses were associated with treatment outcomes in patients with migraine; future studies with large patient samples are warranted.

Neuromagnetic Amygdala Response to Pain-Related Fear as a Brain Signature of Fibromyalgia.

INTRODUCTION: Fibromyalgia (FM) is a chronic pain condition characterized by impaired emotional regulation. This study explored the brain response to pain-related fear as a potential brain signature of FM. METHODS: We used a conditioned fear task and magnetoencephalography to record pain-related fear responses in patients with FM. Two blocks of 30 fear responses were collected to compute the response strength in the first block and the strength difference between the first and second blocks (fear habituation). These measurements were investigated for their clinical relevance and compared with measurements obtained from healthy controls and patients with chronic migraine (CM), a different chronic pain condition often comorbid with FM. RESULTS: Pain-related fear clearly activated the bilateral amygdala and anterior insula in patients with FM (n = 52), patients with CM (n = 50), and the controls (n = 30); the response strength in the first block was consistent across groups. However, fear habituation in the right amygdala decreased in the FM group (vs. CM and control groups, both p ≤ 0.001, no difference between CM and control groups). At the 3-month follow-up, the patients with FM reporting < 30% improvement in pain severity (n = 15) after pregabalin treatment exhibited lower fear habituation in the left amygdala at baseline (vs. ≥ 30% improvement, n = 22, p = 0.019). Receiver operating characteristic analysis confirmed that amygdala fear habituation is a suitable predictor of diagnosis and treatment outcomes of FM (area under the curve > 0.7). CONCLUSIONS: Amygdala activation to pain-related fear is maladaptive and linked to treatment outcomes in patients with FM. Because the aberrant amygdala response was not observed in the CM group, this response is a potential brain signature of FM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT02747940.

Persistence of pregabalin treatment in Taiwan: a nation-wide population-based study.

BACKGROUND: Pregabalin is approved for the treatment of neuropathic pain, fibromyalgia, and seizure disorders, although the pivotal trials were mostly carried out in Europe or North America. The prescribing patterns among different indications in Asia have rarely been explored. METHODS: This was a population-based retrospective cohort study based on the National Health Insurance Research Database in Taiwan. Prescriptions of pregabalin were identified, and data regarding demographics, indications, co-existing diagnoses, and concomitant medications were extracted. Pregabalin users were followed for at least one year, and factors associated with persistence at one year were determined by using multivariate logistic regression analysis. RESULTS: Between June 2012 and December 2016, 114,437 pregabalin users (mean age 60.7 ± 15.4 years, 57.8% female) were identified. The indications included post-herpetic neuralgia (PHN) (30.5%), musculoskeletal diseases other than fibromyalgia (21.2%), fibromyalgia (18.4%), diabetic peripheral neuropathic pain (DPNP) (11.7%) and epilepsy (2.9%). Overall, 62.5% and 6.4% of patients achieved a maximum dose of ≥150 and ≥ 300 mg/day, respectively. The median duration of persistent pregabalin use was 28 days (interquartile range 14-118 days). The one-year persistence rate was 12.1%, and the indications associated with the highest and lowest persistence rates were epilepsy (42.4%) and PHN (6.1%), respectively. Male gender (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.09-1.18), older age (OR 1.01 per year, 95% CI 1.01-1.01), indications other than PHN, especially epilepsy (OR 8.04, 95% CI 7.33-8.81, PHN as reference), and a higher initial dose (OR 1.12 per 75 mg, 95% CI = 1.10-1.15) were associated with persistence at one year, whereas the initial concomitant use of antiviral agents decreased the likelihood (OR 0.41, 95% CI 0.35-0.47). CONCLUSIONS: Pregabalin prescriptions for pain disorders were limited to short-term use, which is consistent around the world. However, the average prescribed dose in Taiwan was lower than those in Western countries, and was frequently below the recommended ranges. Potential causes included the duration of natural history of PHN, and off-label prescriptions for pain in acute herpes zoster, rather than PHN, as well as intolerance to the side effects.

Summative Effects of Vascular Risk Factors on the Progression of Alzheimer Disease.

OBJECTIVES: To investigate the summative effects of vascular risk factors (VRFs) on the progression of Alzheimer disease (AD). DESIGN: Longitudinal follow-up cohort study. SETTING: AD patients from two teaching hospitals in Taiwan with 3-year follow-ups. PARTICIPANTS: A total of 330 AD patients with a mean age of 80.7 years, a mean Mini-Mental State Examination (MMSE) score 18.7, and a mean Clinical Dementia Rating Sum of Boxes (CDRSB) score of 6.9. MEASUREMENTS: All patients completed a clinically functional assessment and a neuropsychological test battery at baseline and yearly follow-ups. The VRF burden was combined into a summative VRF index at baseline (ie, having one, two, or more VRFs); VRFs included coronary heart disease, cardiac arrhythmia, hypertension, cerebrovascular disease, diabetes mellitus, obesity, smoking, and physical inactivity. The generalized estimating equation (GEE) method was used to analyze the correlations between the VRFs and longitudinal MMSE and CDRSB changes. RESULTS: The results of the GEE adjusted for age, years of education, sex, disease duration, baseline MMSE score, time, apolipoprotein E (APOE) ε4 carrier status, use of medications (acetylcholinesterase inhibitors or N-methyl-D-aspartate receptor antagonists), and hospitalization rates and showed that patients with more than three VRFs had more rapid cognitive decline than patients without VRFs (MMSE, P = .02; CDRSB, P = .001) as well as patients with three or fewer VRFs (MMSE, P = .009; CDRSB, P = .02). Subsequent analyses of APOE ε4 carriers with more than three VRFs also showed their more rapid cognitive decline compared with patients without VRFs (MMSE, P = .02; CDRSB, P = .001) and patients with three or fewer VRFs (MMSE, P = .009; CDRSB, P = .02), but no significant difference was found in APOE ε4 noncarriers. CONCLUSION: Multiple VRFs have summative effects on the progression of AD, especially in APOE ε4 carriers. J Am Geriatr Soc 68:129-136, 2019.

NOTCH3 cysteine-altering variant is an important risk factor for stroke in the Taiwanese population.

OBJECTIVE: To test the hypothesis that the prevalence and clinical effect of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been underestimated in Asian populations. METHODS: The Taiwan Biobank, containing 1,517 Taiwanese genome sequences, was queried for pathogenic NOTCH3 cysteine-altering mutations. NOTCH3 mutations identified in the reference population were genotyped in 7,038 stroke- and dementia-free individuals and 800 patients with ischemic stroke. NOTCH3 genotyping, clinical manifestations, and the severity of white matter lesions on MRI were compared between the 2 groups. RESULTS: Three cysteine-altering NOTCH3 variants (p.R544C, p.C853Y, and p.C884Y) were identified from the Taiwan Biobank. We confirmed that the NOTCH3 p.R544C mutation was present in a significant number of individuals in Taiwan, including 60 of the 7,038 healthy controls (0.9%), 17 of the 800 patients with ischemic stroke (2.1%), and 16 of the 245 patients with small vessel occlusion (SVO) stroke (6.5%). The other 2 cysteine-altering mutations were rarely detected. After adjusting for vascular risk factors, harboring the p.R544C variant resulted in a 3.40-fold increased risk for overall stroke and an 11.05-fold increased risk for SVO stroke (p = 0.0001 and 3.9 × 10-10, respectively). Three symptom-free individuals carrying the p.R544C mutation had extensive leukoencephalopathy typical of CADASIL at age 59, 66, and 67, suggesting that p.R544C-related CADASIL could remain subclinical at advanced age. CONCLUSION: The NOTCH3 p.R544C variant is an important risk factor for SVO stroke in Taiwan. Phenotypic variation among individuals carrying a NOTCH3 mutation indicates the existence of disease-modifying factors in CADASIL.

Analgesic effects of repetitive transcranial magnetic stimulation on modified 2010 criteria-diagnosed fibromyalgia: Pilot study.

AIM: Fibromyalgia is often comorbid with depression, and less than half those patients achieve satisfactory improvement after adequate pharmacological intervention. The investigation of repetitive transcranial magnetic stimulation (rTMS) at left dorsolateral prefrontal cortex for modified-2010 American College of Rheumatology (ACR) fibromyalgia and major depressive disorder (MDD) is still in its infancy. METHODS: In this double-blind, randomized, sham-control study, subjects diagnosed with ACR-2010 fibromyalgia and DSM-IV-TR MDD were recruited and received either active or sham interventions for 2 weeks. Hamilton Depression Rating Scale (HDRS) and the 10-cm visual analogue pain scale were evaluated at baseline, week 1, and week 2. Multivariable generalized estimating equations analysis was performed for the association between depression and pain scores at each checkpoint. RESULTS: Twenty subjects were recruited. There was a significant difference over the 2 weeks between the rTMS and sham stimulation groups (P = 0.029), but subgroup analyses were further performed due to significant interaction of group and HDRS on pain outcomes (P = 0.020). The active group had significant improvement in pain at week 2 compared with week 1 (P = 0.021), but the control group did not have any improvement in pain (P = 0.585). Of the mild-moderate depression patients, the pain score in the active group was significantly lower than in the sham group at week 1 (P = 0.001) and at week 2 (P < 0.001). For the severe depression group, there was significantly lower pain over the 2 weeks in the active group (P = 0.045) but the sham group had significantly relapsing pain at week 2 (P < 0.001). CONCLUSION: Left prefrontal rTMS has an analgesic effect in modified-ACR 2010-defined fibromyalgia and MDD patients. Further investigation is required, however, in order to determine how to regulate the different rTMS treatment protocols according to individual baseline depression severity in patients with MDD and fibromyalgia.

Chronic pain as a symptom or a disease: the IASP Classification of Chronic Pain for the International Classification of Diseases (ICD-11).

Chronic pain is a major source of suffering. It interferes with daily functioning and often is accompanied by distress. Yet, in the International Classification of Diseases, chronic pain diagnoses are not represented systematically. The lack of appropriate codes renders accurate epidemiological investigations difficult and impedes health policy decisions regarding chronic pain such as adequate financing of access to multimodal pain management. In cooperation with the WHO, an IASP Working Group has developed a classification system that is applicable in a wide range of contexts, including pain medicine, primary care, and low-resource environments. Chronic pain is defined as pain that persists or recurs for more than 3 months. In chronic pain syndromes, pain can be the sole or a leading complaint and requires special treatment and care. In conditions such as fibromyalgia or nonspecific low-back pain, chronic pain may be conceived as a disease in its own right; in our proposal, we call this subgroup "chronic primary pain." In 6 other subgroups, pain is secondary to an underlying disease: chronic cancer-related pain, chronic neuropathic pain, chronic secondary visceral pain, chronic posttraumatic and postsurgical pain, chronic secondary headache and orofacial pain, and chronic secondary musculoskeletal pain. These conditions are summarized as "chronic secondary pain" where pain may at least initially be conceived as a symptom. Implementation of these codes in the upcoming 11th edition of International Classification of Diseases will lead to improved classification and diagnostic coding, thereby advancing the recognition of chronic pain as a health condition in its own right.

The pathophysiology of episodic cluster headache: Insights from recent neuroimaging research.

Background Cluster headache is a disorder characterized by intermittent, severe unilateral head pain accompanied by cranial autonomic symptoms. Most cases of CH are episodic, manifesting as "in-bout" periods of frequent headache separated by month-to-year-long "out-of-bout" periods of remission. Previous imaging studies have implicated the hypothalamus and pain matrix in the pathogenesis of episodic CH. However, the pathophysiology driving the transition between in- and out-of-bout periods remains unclear. Methods The present study provides a narrative review of previous neuroimaging studies on the pathophysiology of episodic CH, addressing alterations in brain structures, metabolism, and structural and functional connectivity occurring between bout periods. Results Although the precise brain structures responsible for episodic CH are unknown, major roles are indicated for the posterior hypothalamus (especially in acute attacks), the pain neuromatrix with an emphasis on central descending pain modulation, and non-traditional pain processing networks including the occipital, cerebellar, and salience networks. These areas are potentially related to dynamic transitioning between in- and out-of-bout periods. Conclusion Recent progress in magnetic resonance imaging of episodic CH has provided additional insights into dynamic bout-associated structural and functional connectivity changes in the brain, especially in non-traditional pain processing network areas. These areas warrant future investigations as targets for neuromodulation in patients with CH.

Genome-wide association study identifies novel susceptibility loci for migraine in Han Chinese resided in Taiwan.

Background Susceptibility genes for migraine, despite it being a highly prevalent and disabling neurological disorder, have not been analyzed in Asians by genome-wide association study (GWAS). Methods We conducted a two-stage case-control GWAS to identify susceptibility genes for migraine without aura in Han Chinese residing in Taiwan. In the discovery stage, we genotyped 1005 clinic-based Taiwanese migraine patients and 1053 population-based sex-matched controls using Axiom Genome-Wide CHB Array. In the replication stage, we genotyped 27 single-nucleotide polymorphisms with p < 10-4 in 1120 clinic-based migraine patients and 604 sex-matched normal controls by using Sequenom. Variants at LRP1, TRPM8, and PRDM, which have been replicated in Caucasians, were also genotyped. Results We identified a novel susceptibility locus (rs655484 in DLG2) that reached GWAS significance level for migraine risk in Han Chinese ( p = 1.45 × 10-12, odds ratio [OR] = 2.42), and also another locus (rs3781545in GFRA1) with suggestive significance ( p = 1.27 × 10-7, OR = 1.38). In addition, we observed positive association signals with a similar trend to the associations identified in Caucasian GWASs for rs10166942 in TRPM8 (OR = 1.33, 95% confidence interval [CI] = 1.14-1.54, Ppermutation = 9.99 × 10-5; risk allele: T) and rs1172113 in LRP1 (OR = 1.23, 95% CI = 1.04-1.45, Ppermutation = 2.9 × 10-2; risk allele: T). Conclusion The present study is the first migraine GWAS conducted in Han-Chinese and Asians. The newly identified susceptibility genes have potential implications in migraine pathogenesis. DLG2 is involved in glutamatergic neurotransmission, and GFRA1 encodes GDNF receptors that are abundant in CGRP-containing trigeminal neurons. Furthermore, positive association signals for TRPM8 and LRP1 suggest the possibility for common genetic contributions across ethnicities.