A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression.

Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common SNP in the third intron of the PHACTR1 gene, as the putative causal variant. Epigenomic data from human tissue revealed an enhancer signature at rs9349379 exclusively in aorta, suggesting a regulatory function for this SNP in the vasculature. CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379 regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of PHACTR1. The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated diseases. Overall, these data illustrate the integration of genetic, phenotypic, and epigenetic analysis to identify the biologic mechanism by which a common, non-coding variant can distally regulate a gene and contribute to the pathogenesis of multiple vascular diseases.

Clinical Potential of Adrenomedullin Signaling in the Cardiovascular System.

Numerous clinical studies have revealed the utility of circulating AM (adrenomedullin) or MR-proAM (mid-regional proAM 45-92) as an effective prognostic and diagnostic biomarker for a variety of cardiovascular-related pathophysiologies. Thus, there is strong supporting evidence encouraging the exploration of the AM-CLR (calcitonin receptor-like receptor) signaling pathway as a therapeutic target. This is further bolstered because several drugs targeting the shared CGRP (calcitonin gene-related peptide)-CLR pathway are already Food and Drug Administration-approved and on the market for the treatment of migraine. In this review, we summarize the AM-CLR signaling pathway and its modulatory mechanisms and provide an overview of the current understanding of the physiological and pathological roles of AM-CLR signaling and the yet untapped potentials of AM as a biomarker or therapeutic target in cardiac and vascular diseases and provide an outlook on the recently emerged strategies that may provide further boost to the possible clinical applications of AM signaling.

Comparative efficacy, quality of life, safety, and tolerability of atogepant and rimegepant in migraine prevention: A matching-adjusted indirect comparison analysis.

BACKGROUND: Comparative evaluations of preventive migraine treatments can help inform clinical decision making for managing migraine in clinical practice. METHODS: An anchored matching-adjusted indirect comparison analysis was conducted using pooled participant-level data from two phase 3 atogepant trials (ADVANCE and PROGRESS) and one phase 2/3 rimegepant trial (BHV3000-305) to evaluate the relative efficacy and safety/tolerability of atogepant and rimegepant as preventive migraine treatments. Participants receiving atogepant 60 mg once daily, rimegepant orally disintegrating tablet 75 mg once every other day, and placebo were included. Only participants meeting the BHV3000-305 inclusion/exclusion criteria were analyzed: ≥6 monthly migraine days and ≤18 monthly headache days at baseline. The primary efficacy assessment of interest was change in monthly migraine days across weeks 1-12. RESULTS: There were 252 participants in the atogepant group and 348 in the rimegepant group. Across weeks 1-12, atogepant 60 mg demonstrated a significantly greater reduction in mean monthly migraine days compared with rimegepant 75 mg (mean difference [95% CI]: -1.65 [-2.49, -0.81]; p < 0.001). Both atogepant and rimegepant demonstrated similar safety/tolerability profiles. CONCLUSION: In this matching-adjusted indirect comparison analysis, oral atogepant 60 mg once daily demonstrated a significantly greater reduction in monthly migraine days compared with rimegepant 75 mg orally disintegrating tablet once every other day.

Characterizing gaps in the preventive pharmacologic treatment of migraine: Multi-country results from the CaMEO-I study.

OBJECTIVE: To analyze data from the Chronic Migraine Epidemiology and Outcomes-International (CaMEO-I) Study in order to characterize preventive medication use and identify preventive usage gaps among people with migraine across multiple countries. BACKGROUND: Guidelines for the preventive treatment of migraine are available from scientific organizations in various countries. Although these guidelines differ among countries, eligibility for preventive treatment is generally based on monthly headache day (MHD) frequency and associated disability. The overwhelming majority of people with migraine who are eligible for preventive treatment do not receive it. METHODS: The CaMEO-I Study was a cross-sectional, observational, web-based panel survey study performed in six countries: Canada, France, Germany, Japan, the United Kingdom, and the United States. People were invited to complete an online survey in their national language(s) to identify those with migraine according to modified International Classification of Headache Disorders, 3rd edition, criteria. People classified with migraine answered questions about current and ever use of both acute and preventive treatments for migraine. Available preventive medications for migraine differed by country. MHD frequency and associated disability data were collected. The American Headache Society (AHS) 2021 Consensus Statement algorithm was used to determine candidacy for preventive treatment (i.e., ≥3 monthly MHDs with severe disability, ≥4 MHDs with some disability, or ≥6 MHDs regardless of level of disability). RESULTS: Among 90,613 valid completers of the screening survey, 14,492 met criteria for migraine and completed the full survey, with approximately 2400 respondents from each country. Based on the AHS consensus statement preventive treatment candidacy algorithm, averaging across countries, 36.2% (5246/14,492) of respondents with migraine qualified for preventive treatment. Most respondents (84.5% [4431/5246]) who met criteria for preventive treatment according to the AHS consensus statement were not using a preventive medication at the time of the survey. Moreover, 19.3% (2799/14,492) of respondents had ever used preventive medication (ever users); 58.1% (1625/2799) of respondents who reported ever using a preventive medication for migraine were still taking it. Of the respondents who were currently using a preventive medication, 50.2% (815/1625) still met the criteria for needing preventive treatment based on the AHS consensus statement. CONCLUSIONS: Most people with migraine who qualify for preventive treatment are not currently taking it. Additionally, many people currently taking preventive pharmacologic treatment still meet the algorithm criteria for needing preventive treatment, suggesting inadequate benefit from their current regimen.

Characterizing neck pain during headache among people with migraine: Multicountry results from the Chronic Migraine Epidemiology and Outcomes - International (CaMEO-I) cross-sectional study.

OBJECTIVE: To assess the prevalence and impact of neck pain during headache among respondents with migraine in the multicountry Chronic Migraine Epidemiology and Outcomes - International (CaMEO-I) Study. BACKGROUND: Neck pain among individuals with migraine is highly prevalent and contributes to disability. METHODS: The CaMEO-I was a prospective, cross-sectional, web-based study conducted in Canada, France, Germany, Japan, United Kingdom, and the United States. A demographically representative sample of participants from each country completed a screening survey to evaluate headache characteristics. Respondents with headache were identified as having migraine or non-migraine headache based on modified International Classification of Headache Disorders, third edition, criteria; those with migraine completed a detailed survey with migraine-specific assessments. Results were stratified by the presence or absence of neck pain with headache (NPWH). For these analyses, data were pooled across the six countries. RESULTS: Of 51,969 respondents who reported headache within the past 12 months, 14,492 (27.9%) were classified as having migraine; the remaining 37,477 (72.1%) had non-migraine headache. Overall, 9896/14,492 (68.3%) of respondents with migraine headache reported NPWH, which was significantly higher (p < 0.001) than the proportion of respondents with non-migraine headache who reported NPWH (13,536/37,477 [36.1%]). Among respondents with migraine, moderate-to-severe disability was significantly more prevalent for those with NPWH versus without (47.7% [4718/9896] vs. 28.9%, p < 0.001). Respondents with NPWH versus without also had significantly greater work productivity losses, at a median (interquartile range [IQR]) of 50.0 (20.0, 71.3) vs. 30.0 (0.0, 60.0) (p < 0.001), lower quality of life (Migraine-Specific Quality of Life questionnaire version 2.1, median [IQR] Role Function-Restrictive domain score 60.0 [42.9, 74.3] vs. 68.6 [54.3, 82.9], p < 0.001), higher prevalence of depression and anxiety symptoms (depression, 40.2% [3982/9896] vs. 28.2% [1296/4596], p < 0.001); anxiety, 41.2% [4082/9896] vs. 29.2% [1343/4596], p < 0.001), higher prevalence of cutaneous allodynia during headache (54.0% [5345/9896] vs. 36.6% [1681/4596], p < 0.001), and higher prevalence of poor acute treatment optimization (61.1% [5582/9129] vs. 53.3% [2197/4122], p < 0.001). CONCLUSIONS: Nearly 70% of respondents with migraine reported NPWH. Individuals with migraine with neck pain during their headaches had greater disability, depression, anxiety, and cutaneous allodynia (during headache) than those without neck pain during their headaches. They also had diminished quality of life and work productivity, and poorer response to acute treatment compared with those without neck pain.

Efficacy of various exercise interventions for migraine treatment: A systematic review and network meta-analysis.

OBJECTIVE: To compare various exercise modalities' efficacy on migraine frequency, intensity, duration, and disability. BACKGROUND: Exercise has been shown to be an effective intervention to reduce migraine symptoms and disability; however, no clear evidence exists regarding the most effective exercise modalities for migraine treatment. METHODS: A systematic review was performed in PubMed, PEDro, Web of Science, and Google Scholar. Clinical trials that analyzed the efficacy of various exercise modalities in addressing the frequency, intensity, duration, and disability of patients with migraine were included. Eight network meta-analyses based on frequentist (F) and Bayesian (B) models were developed to estimate the direct and indirect evidence of various exercise modalities. Standardized mean difference (SMD) and 95% confidence (CI) and credible intervals (CrI) were calculated for each treatment effect based on Hedge's g and p scores to rank the modalities. RESULTS: We included 28 studies with 1501 migraine participants. Yoga (F: SMD -1.30; 95% CI -2.09, -0.51; B: SMD -1.33; 95% CrI -2.21, -0.45), high-intensity aerobic exercise (F: SMD -1.30; 95% CI -2.21, -0.39; B: SMD -1.17; 95% CrI -2.20, -0.20) and moderate-intensity continuous aerobic exercise (F: SMD -1.01; 95% CI -1.63, -0.39; B: SMD -1.06; 95% CrI -1.74, -0.38) were significantly superior to pharmacological treatment alone for decreasing migraine frequency based on both models. Only yoga (F: SMD -1.40; 95% CI -2.41, -0.39; B: SMD -1.41; 95% CrI -2.54, -0.27) was significantly superior to pharmacological treatment alone for reducing migraine intensity. For diminishing migraine duration, high-intensity aerobic exercise (F: SMD -1.64; 95% CI -2.43, -0.85; B: SMD -1.56; 95% CrI -2.59, -0.63) and moderate-intensity continuous aerobic exercise (SMD -0.96; 95% CI -1.50, -0.41; B: SMD -1.00; 95% CrI -1.71, -0.31) were superior to pharmacological treatment alone. CONCLUSION: Very low-quality evidence showed that yoga, high- and moderate-intensity aerobic exercises were the best interventions for reducing migraine frequency and intensity; high- and moderate-intensity aerobic exercises were best for decreasing migraine duration; and moderate-intensity aerobic exercise was best for diminishing disability.

Persistent headache attributed to past ischemic stroke: A prospective cohort study.

OBJECTIVE: To assess the incidence, characteristics, and risk factors for developing persistent headache attributed to past ischemic stroke. BACKGROUND: Although the most recent International Classification of Headache Disorders has recognized the existence of persistent headache attributed to past ischemic stroke, there has been limited research in this area. METHODS: This was a prospective cohort study. We initially assessed patients hospitalized with ischemic stroke admitted within 72 h of symptom onset. All patients underwent diffusion-weighted magnetic resonance imaging. These patients were re-interviewed by telephone 1 year after the stroke. Semi-structured questionnaires, the National Institutes of Health Stroke Scale (NIHSS), and six-item Headache Impact Test were used. RESULTS: A total of 119 participants answered the interview conducted 1 year after the stroke. The mean (standard deviation) age was 64 (13.1) years, 82/119 (68.9%) were female, and the median (interquartile range) NIHSS score was 2 (1.0-4.0). The incidence rate of persistent headache attributed to past ischemic stroke was 12/119 (10.1%; 95% confidence interval [CI] 5.3-17.0%). The most frequent pattern presented was a migraine-like pattern in seven of the 12 (58.3%) patients, which had a substantial/severe impact on five of the 12 (41.7%). For most patients this headache continued, although it began to improve. Previous migraine (odds ratio 7.1, 95% CI 1.06-50.0; p = 0.043) and headache intensity in the acute phase of stroke (odds ratio 1.75, 95% CI 1.13-2.7; p = 0.012) were associated with the occurrence of persistent headache attributed to past ischemic stroke. CONCLUSION: Persistent headache attributed to past ischemic stroke is a frequent complication after stroke. It often has a significant impact on patients' lives and presents a migraine-like pattern as its most frequent phenotype.

Individualized spectral filters alleviate persistent photophobia, headaches and migraines in active duty military and Veterans following brain trauma.

PURPOSE: Consistent with association between photophobia and headache, growing evidence suggests an underlying causal relationship between light sensitivity and central pain. We investigated whether an intervention to regulate light sensitivity by filtering only wavelengths causing difficulties for the specific individual could alleviate headaches/migraines resulting from traumatic brain injury (TBI). METHODS: Secondary data analysis of a clinical database including N = 392 military personnel (97% men, 3% women), ranging in age from 20 to 51 years, diagnosed with TBI, persistent headaches/migraines, and light sensitivity. The average elapsed time from TBI diagnosis to intervention was 3 years. Headache/migraine severity, frequency, medication use, and difficulties related to daily functioning were assessed pre and 4-12 weeks post-intervention with individualized spectral filters. RESULTS: Monthly migraine frequency decreased significantly from an average of 14.8 to 1.9, with 74% reporting no migraines post-intervention. Prescription and over-the-counter medication use decreased by more than 70%. Individuals also reported significant improvement in light sensitivity, headaches/migraine severity, and physical and perceptual symptoms. CONCLUSIONS: Wearing individualized spectral filters was associated with symptom relief, increased subjective quality of reported health and well-being, and decreased objective medication use for TBI-related persistent headaches/migraines. These results support a suggested relationship between dysregulated light sensitivity and central regulation of pain.

Frequency and Size of In Situ Thrombus Within Patent Foramen Ovale.

BACKGROUND: High-resolution optical coherence tomography can detect in situ thrombi within patent foramen ovale (PFO), which can become a dangerous embolic source. This study aimed to investigate the frequency and size of in situ thrombus within PFO using optical coherence tomography. METHODS: The cross-sectional study was conducted at Fuwai Hospital (Beijing, China) between 2020 and 2021. From 528 consecutive patients with PFO, 117 (age, 34.33 [SD, 11.30] years) without known vascular risk factors were included; according to PFO-related symptoms, they were divided into the stroke (n=43, including 5 patients with transient ischemic attack), migraine (n=49) and asymptomatic (n=25) groups. Optical coherence tomography was used to evaluate in situ thrombi and abnormal endocardium within PFO. Univariable analysis and a logistic model were used to evaluate the association between stroke and in situ thrombus; age, sex, body mass index, and antithrombotic therapy were included as covariates. RESULTS: Antithrombotic therapy was used more frequently in the stroke group than in the migraine group (76.7% versus 12.2%; P<0.001). In situ PFO thrombi were detected in 36 (83.7%), 28 (57.1%), and 0 (0.0%) patients from the stroke, migraine, and asymptomatic groups, respectively (P<0.001). Between the stroke and migraine groups, there was no significant difference in the median (interquartile range) thrombus number per patient (7 [3-12] versus 2 [0-10]; P=0.199), maximum thrombus diameter (0.35 [0.20-0.46] versus 0.21 [0-0.68] mm; P=0.597), or total thrombus volume (0.02 [0.01-0.05] versus 0.01 [0-0.05] mm3; P=0.386). Additionally, in situ thrombus was significantly associated with stroke risk (odds ratio, 4.59 [95% CI, 1.26-16.69]). Abnormal endocardium within PFO occurred in patients with in situ thrombi (71.9%) but not in those without. During optical coherence tomography examination, migraine occurred in 2 patients with in situ thrombi. CONCLUSIONS: The frequency of in situ thrombus was extremely high in stroke and migraine groups, while none of the asymptomatic individuals presented with an in situ thrombus. In situ thrombus formation may play a role in patients with PFO-associated stroke or migraines and have therapeutic implications. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04686253.

Neurological and psychiatric comorbidities of migraine: Concepts and future perspectives.

BACKGROUND: This narrative review aims to discuss several common neurological and psychiatric disorders that show comorbidity with migraine. Not only can we gain pathophysiological insights by studying these disorders, comorbidities also have important implications for treating migraine patients in clinical practice. METHODS: A literature search on PubMed and Embase was conducted with the keywords "comorbidity", "migraine disorders", "migraine with aura", "migraine without aura", "depression", "depressive disorders", "epilepsy", "stroke", "patent foramen ovale", "sleep wake disorders", "restless legs syndrome", "genetics", "therapeutics". RESULTS: Several common neurological and psychiatric disorders show comorbidity with migraine. Major depression and migraine show bidirectional causality and have shared genetic factors. Dysregulation of both hypothalamic and thalamic pathways have been implicated as a possibly cause. The increased risk of ischaemic stroke in migraine likely involves spreading depolarizations. Epilepsy is not only bidirectionally related to migraine, but is also co-occurring in monogenic migraine syndromes. Neuronal hyperexcitability is an important overlapping mechanism between these conditions. Hypothalamic dysfunction is suggested as the underlying mechanism for comorbidity between sleep disorders and migraine and might explain altered circadian timing in migraine. CONCLUSION: These comorbid conditions in migraine with distinct pathophysiological mechanisms have important implications for best treatment choices and may provide clues for future approaches.

Assessing the influence of migraine on ischemic penumbra and on the prognosis of ischemic stroke: A prospective cohort study.

INTRODUCTION: There is controversy as to whether migraine affects the behavior of ischemic penumbra during the acute phase of an ischemic stroke, thereby accelerating the formation of cerebral infarction. OBJECTIVES: To assess whether migraine modifies the existence and volume of the divergence between the areas of diffusion and perfusion in the stroke (the penumbra) and whether migraine implies a poorer prognosis after the stroke. METHODS: This was a prospective cohort study. We included hospitalized patients with ischemic stroke within 72 h of symptom onset (convenience sampling). A semi-structured questionnaire, the National Institute of Health Stroke Scale, and the modified Rankin Scale (mRS) were used. Patients underwent magnetic resonance imaging (MRI) of the brain with diffusion and with perfusion. Patients were assessed by telephone 3 months after the stroke to determine the prognosis. Scores of > 2 on the mRS were considered to have a poor prognosis. RESULTS: A total of 221 patients were included, 131/221 (59%) of whom were male, and with a mean (SD) age of 68.2 (13.8) years. Ischemic penumbra analysis was performed in 118 patients. There was no association between migraine and the absence of ischemic penumbra (16/63 [25%] vs. 12/55 [22%]; odds ratio 1.22, 95% confidence interval 0.52-2.87; p = 0.64). There was no difference in stroke volume between those with and without migraine (median [interquartile range] 1.0 [0.4-7.9] vs. 1.8 [0.3-9.4] cm3 ; p = 0.99). Migraine was not associated with the stroke prognosis after multivariable analysis. CONCLUSION: Migraine is not associated with the absence of ischemic penumbra, the volume of the ischemic penumbra, or the stroke prognosis.

Headache and systemic lupus erythematosus: A narrative review.

OBJECTIVE: To review the epidemiology, the differential diagnosis, and the clinical and laboratory factors associated with the care management of headaches in patients with systemic lupus erythematosus (SLE). BACKGROUND: SLE is a chronic autoimmune disease and in 12%-95% of patients, the nervous system is involved. Headache is a frequently reported, although nonspecific, symptom that may potentially represent serious underlying diagnoses. Primary headaches may also occur in these patients, thereby causing a negative and significant impact on their quality of life. METHODS: This is a narrative review. A literature review was conducted on the PubMed platform using the following terms: (1) headache and (2) lupus. All articles considered relevant were included. No limitations were imposed for the publication date. RESULTS: Headache is a frequent symptom in patients with SLE. Although its prevalence is similar to the general population, headaches nonetheless tend to have a greater negative impact on these patients. Patients with SLE are more likely to experience headache due to vascular diseases such as cerebral venous sinus thrombosis, stroke, reversible cerebral vasoconstriction syndrome, posterior reversible encephalopathy syndrome, and vasculitis. Aseptic meningitis, neuroinfections, intracranial neoplasms, and intracranial hypertension or hypotension may also be a cause of headache in these patients. Although used in disease activity scores, the concept of lupus headache is controversial. CONCLUSIONS: Headache is a frequent symptom in patients with SLE. An appropriate approach enables the potentially serious conditions, which are the causes of secondary headaches, to be recognized and treated, together with an appropriate diagnosis and treatment of primary headaches.

Conceptualising migraine attacks from a biopsychosocial model using qualitative and functional behavioural analysis.

OBJECTIVE: The aim of this study was to explore patients' experiences and management of pain in connection with a migraine attack in episodic migraine. DESIGN, SETTING AND SUBJECTS: This qualitative study used a semi-structured interview format based on functional behavioural analysis as commonly used in cognitive behavioural therapy. We interviewed eight participants and analysed their responses using systematic text condensation. RESULTS: Participants' descriptions of their experiences and management of pain from episodic migraine were sorted into three description First physical sensations, Automatic reactions and Acts according to the interpretation. CONCLUSION: From a biopsychosocial perspective, a migraine attack is much more complex than just an experience of pain. The purely biological pain prompts a number of automatic reactions leading to strategies for pain management.

Functional behavioural analysis can increase our understanding of experiences during a migraine attack from a biopsychosocial pain perspective.Several pain mechanisms appear to be relevant during the experience of a migraine attack than are described in the diagnostic criteria for migraine.Pain management consists of a chain of behaviours, approaches to the migraine attack and medication and the consequences of pain management.Knowledge and understanding of patients' experiences of pain and pain management during a migraine attack is an important tool in the biopsychosocial model.

Are central sensitization symptoms and psychosocial alterations interfering in the association between painful TMD, migraine, and headache attributed to TMD?

OBJECTIVE: To determine if somatosensory function and symptoms related to central sensitization (CS) differed in individuals with painful temporomandibular disorders (TMD) according to the presence of migraine (MIG) or MIG + headache attributed to TMD (HAT). MATERIALS AND METHODS: This study evaluated 92 adults (20-65 years), presenting painful TMD. Standard diagnostic criteria were applied to classification of painful TMD, MIG, and HAT. CS was assessed through the central sensitization inventory (CSI), wind-up ratio (WUR), pressure pain thresholds (PPT), and the conditioned pain modulation test (CPM). Psychosocial factors were evaluated by validated instruments. RESULTS: There was a significant difference regarding gender, with more women in the group TMD + MIG + HAT (p = 0.028). TMD + MIG and TMD + MIG + HAT had significantly lower PPTs than the TMD group. No group differences were found for the WUR, CPM, or CSI. TMD + MIG + HAT had higher chronic pain intensity (p = 0.001), disability points (p = 0.045), graded chronic pain scale (p = 0.007), and higher somatization (NSPS) scores (p = 0.012), compared to the other groups. CONCLUSION: Mechanical hyperalgesia was more pronounced in the group with the highest pain and somatization scores, while CPM and WUR did not differ between groups. Altered somatosensory function and CS may partially underlie the pathophysiology of overlapping TMD pain conditions, pointing towards additive effects of comorbid head pains. CLINICAL RELEVANCE: Our results demonstrate the importance of considering the association of primary and secondary headaches during TMD assessment and its implications for maintaining the signs and symptoms of CS. This can influence the conduct of treatment, which must be multidisciplinary, and must include management of mechanisms related to CS.

[Complementary and supplementary procedures in the treatment of headache]. / Komplementäre und ergänzende Verfahren in der Kopfschmerztherapie.

In Germany, headache is one of the illnesses that most frequently leads to health impairments and to consultation with physicians. Even in children, headache is often associated with restricted activities of daily life. Nevertheless, the level of care for headache disorders is disproportionate to the medical needs. As a result, patients regularly use complementary and supportive therapeutic procedures. This review shows the procedures currently used for primary headache in childhood and adulthood, the methodological approaches and existing scientific evidence. The safety of the therapeutic options is also classified. These methods include physiotherapy, neural therapy, acupuncture, homeopathy, phytotherapy and the intake of dietary supplements. For children and adolescents with headaches, there are studies in the field of dietary supplements for coenzyme Q10, riboflavin, magnesium and vitamin D, which indicate specific effects in the reduction of headaches.

[Transcranial alternating current stimulation to modulate oscillations in pain disorders]. / Transkranielle Wechselstromstimulation zur Modulation von Oszillationen bei Schmerzerkrankungen.

BACKGROUND: Chronic pain is a common health problem, for which the treatment is complex and challenging. Non-invasive brain stimulation techniques, specifically transcranial alternating current stimulation (tACS), show promise as a well-tolerated new therapeutic modality with few side effects. This is supported by growing evidence of an association between altered neuronal oscillations and chronic pain. However, to date, only a handful of studies with variable methodology have evaluated tACS for potential applicability to patients with chronic pain. OBJECTIVES: Presentation and discussion of the evidence thus far, evaluation of a potential therapeutic benefit for chronic pain patients. MATERIALS AND METHODS: Literature search in MEDLINE, Embase, Cochrane Library, and Google Scholar databases. RESULTS: To date, tACS for chronic pain therapy has been investigated in only three studies with very different methodological approaches and quality. DISCUSSION: These data currently do not provide sufficient evidence for the therapeutic use of tACS for chronic pain therapy. Future studies may address the question of a therapeutic benefit of tACS for this indication utilizing improved stimulation techniques and considering existing recommendations for the design and conduct of tACS studies.

[Clinical use of botulinum toxin type A in pain medicine]. / Klinische Anwendung von Botulinumtoxin Typ A in der Schmerzmedizin.

Botulinum toxin has been used for decades in the treatment of a variety of painful diseases. Botulinum toxin not only blocks neuromuscular transmission, but also the secretion of neuropeptides, such as substance P, glutamate and calcitonin gene-related peptide (CGRP) and thus inhibits neurogenic inflammation. In addition, it has a modulatory pain-relieving effect via retrograde transport into the central nervous system. In addition to approval for the treatment of dystonia or spasticity, onabotulinum toxin A is also approved for the prophylaxis of chronic migraine if the oral prophylactic migraine medication has had an insufficient effect or has not been tolerated. In addition, botulinum toxin is also recommended in guidelines as a third-line treatment for neuropathic pain, but in Germany this is an off-label application. This article provides an overview of the current clinically relevant areas of application of botulinum toxin in the field of pain medicine.

[Temporary and persistent visual phenomena in neurology]. / Passagere und anhaltende visuelle Phänomene in der Neurologie.

Temporary and persistent visual phenomena are a frequent reason for a neurological presentation. The diagnosis can usually be made with the help of a structured anamnesis with determination of the time of onset, the course and symptoms as well as the monocular vs. binocular manifestation. The visual aura in migraine is certainly the most frequent entity to be differentiated. In particular, persistent visual phenomena such as visual snow syndrome, hallucinogen persisting perception disorder and the Charles Bonnet syndrome (CBS) seem to be underdiagnosed in clinical practice for various reasons and are probably not that rare. Instrumental diagnostics are mostly used for exclusion diagnostics and are a component of a complete patient education, but can be indicative for certain questions (CBS, epilepsy). This article presents the most frequent visual phenomena from the neurological practice and their differential diagnoses, guided by a case history.

Increased MRI-based Brain Age in chronic migraine patients.

INTRODUCTION: Neuroimaging has revealed that migraine is linked to alterations in both the structure and function of the brain. However, the relationship of these changes with aging has not been studied in detail. Here we employ the Brain Age framework to analyze migraine, by building a machine-learning model that predicts age from neuroimaging data. We hypothesize that migraine patients will exhibit an increased Brain Age Gap (the difference between the predicted age and the chronological age) compared to healthy participants. METHODS: We trained a machine learning model to predict Brain Age from 2,771 T1-weighted magnetic resonance imaging scans of healthy subjects. The processing pipeline included the automatic segmentation of the images, the extraction of 1,479 imaging features (both morphological and intensity-based), harmonization, feature selection and training inside a 10-fold cross-validation scheme. Separate models based only on morphological and intensity features were also trained, and all the Brain Age models were later applied to a discovery cohort composed of 247 subjects, divided into healthy controls (HC, n=82), episodic migraine (EM, n=91), and chronic migraine patients (CM, n=74). RESULTS: CM patients showed an increased Brain Age Gap compared to HC (4.16 vs -0.56 years, P=0.01). A smaller Brain Age Gap was found for EM patients, not reaching statistical significance (1.21 vs -0.56 years, P=0.19). No associations were found between the Brain Age Gap and headache or migraine frequency, or duration of the disease. Brain imaging features that have previously been associated with migraine were among the main drivers of the differences in the predicted age. Also, the separate analysis using only morphological or intensity-based features revealed different patterns in the Brain Age biomarker in patients with migraine. CONCLUSION: The brain-predicted age has shown to be a sensitive biomarker of CM patients and can help reveal distinct aging patterns in migraine.

Prescription of therapeutic exercise in migraine, an evidence-based clinical practice guideline.

The main objective of this clinical practice guideline is to provide a series of recommendations for healthcare and exercise professionals, such as neurologists, physical therapists, and exercise physiologists, regarding exercise prescription for patients with migraine.This guideline was developed following the methodology and procedures recommended in the Appraisal of Guidelines for Research and Evaluation (AGREE). The quality of evidence and strength of recommendations were evaluated with the Scottish Intercollegiate Guidelines Network (SIGN). A systematic literature review was performed and an established appraisal process was employed to rate the quality of relevant scientific research (Grading of Recommendations Assessment, Development, and Evaluation methodology).The evaluation of the current evidence, the elaboration of the grades of recommendation, and their validation show a B grade of recommendation for aerobic exercise, moderate-continuous aerobic exercise, yoga, and exercise and lifestyle recommendations for the improvement of symptoms, disability, and quality of life in patients with migraine. Relaxation techniques, high-intensity interval training, low-intensity continuous aerobic exercise, exercise and relaxation techniques, Tai Chi, and resistance exercise obtained a C grade of recommendation for the improvement of migraine symptoms and disability.