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Background: We aimed to explore whether erenumab, a monoclonal antibody targeting the calcitonin gene-related peptide receptor, could exert a central effect on brain network function in migraine, and investigate the persistence of such an effect following treatment discontinuation., Methods: This was a randomized, double-blind, placebo-controlled, multicenter trial with a crossover design performed in adult episodic migraine patients with previous treatment failure. Patients were randomized (1:1) to 12 weeks of erenumab 140 mg or placebo, followed by a 12-week crossover. Resting state (RS) functional connectivity (FC) changes of brain networks involved in migraine were investigated using a seed-based correlation approach., Results: Sixty-one patients were randomized to treatment. In each treatment sequence, 27 patients completed the visit at week 12. Forty-four enrolled patients, 22 in each treatment sequence, completed the study procedures with no major protocol violations. We observed a carry-over effect of erenumab during the placebo treatment and therefore data analysis was performed as a parallel comparison of erenumab vs placebo of the first 12 weeks of treatment. From baseline to week 12, compared to placebo, patients receiving erenumab showed RS FC changes within the cerebellar, thalamic and periaqueductal gray matter networks, significantly associated with clinical improvement. Compared to non-responders, patients achieving a 50% reduction in migraine days had distinct patterns of thalamic and visual network RS FC. Brain RS FC changes reversed when erenumab was stopped. A lower baseline RS FC of the pontine network identified patients responding to erenumab., Conclusion: Erenumab modulates RS FC of networks involved in migraine pathophysiology. In line with clinical response, erenumab-induced brain RS FC changes tend to reverse when treatment is stopped., (© 2023. The Author(s).)

Background: The ongoing Pan-European Real Life (PEARL) phase 4 study is evaluating fremanezumab effectiveness and safety for the prevention of episodic and chronic migraine. This interim analysis reports primary, secondary and exploratory endpoints from when 500 participants completed at least six months of treatment., Methods: Adults with episodic migraine or chronic migraine maintaining daily headache diaries were enrolled upon initiation of fremanezumab. Primary endpoint: proportion of participants with ≥50% reduction in monthly migraine days during the six-month period after fremanezumab initiation. Secondary endpoints: mean change from baseline across months 1-12 in monthly migraine days, acute migraine medication use, and headache-related disability. Exploratory endpoint: mean change in headache severity from baseline across months 1-12. Safety was assessed through adverse events reported., Results: Overall, 897 participants were enrolled and 574 included in the effectiveness analyses (episodic migraine, 25.8%; chronic migraine, 74.2%). Of participants with data available, 175/313 (55.9%) achieved ≥50% monthly migraine days reduction during the six-month period post-initiation. Across months 1-12, there were sustained reductions in mean monthly migraine days, acute medication use, disability scores, and headache severity. Few adverse events were reported., Conclusion: PEARL interim results support the effectiveness and safety of fremanezumab for migraine prevention in a real-world population across several European countries.Trial registration: encepp.eu: EUPAS35111., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MA reports personal fees and PI in clinical trials for AbbVie, Amgen, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals; and research grants from Lundbeck Foundation, Novo Nordisk Foundation, and Novartis. DDM has received honoraria, research, and travel grants from Allergan/Abbvie, Amgen, Biogen, Cefaly, Genesis Pharma, Electrocore, Eli Lilly, Lundbeck, Merk-Serono, Mertz, Novartis, Roche, Sanofi, Specifar, and Teva Pharmaceuticals; participated in clinical trials for Amgen, Cefaly, Electrocore, Eli Lilly, Genesis Pharma, Lundbeck, Mertz, Novartis, Specifar, and Teva Pharmaceuticals as principal investigator; and is President of the board of the Hellenic Headache Society and Co-chairman of the management group of the Headache Panel at the European Academy of Neurology. FMA reports lectures, advisory boards, and/or PI in clinical trials for Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals. PK, VRC, and AHA are employees and/or shareholders of Teva Pharmaceuticals. LL is a former employee of Teva Pharmaceuticals. CJS reports consulting, advisory boards, presentations, and travel support from Novartis, Eli Lilly, Teva Pharmaceuticals, AbbVie, Allergan, Almirall, Amgen, Lundbeck, MindMed, and Grünenthal; is a part-time employee of Zynnon; and reports research support from the Swiss Heart Foundation, Eye on Vision Foundation, Baasch-Medicus Foundation, and German Migraine and Headache Society. GS reports advisory boards and/or PI in clinical trials for AbbVie, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals; and research support from Vinnova (Sweden’s innovation agency), Lund University, and the Swedish Neurological Association. PPR reports grant/research support from AbbVie, AGAUR, EraNet NEURON, Instituto Investigación Carlos III, MINECO, Novartis, RIS3CAT FEDER, and Teva Pharmaceuticals; and consultancy or education for AbbVie, Amgen, Biohaven, Chiesi, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals. PJD reports educational meetings and/or collaboration in clinical trials for Allergan/AbbVie, electroCore, Novartis, Teva Pharmaceuticals, and Lundbeck. TN reports consulting, speaking fees, and travel grants from Eli Lilly, Glenmark, Lundbeck, Novartis, Pfizer, St. Jude Medical, Teva Pharmaceuticals, and UCB; and advisory boards or PI in clinical trials for AbbVie, Amgen, Eli Lilly, Lundbeck, Neurocrine, Novartis, Teva Pharmaceuticals, and UCB. ACP reports lectures, advisory boards, and/or PI in clinical trials for Allergan, AbbVie, Pfizer, Teva Pharmaceuticals, Novartis, Lundbeck, Eli Lilly, and Roche. IPM reports lectures, advisory boards, and/or PI in clinical trials for Allergan-AbbVie, Teva Pharmaceuticals, Novartis, Lundbeck, and Eli Lilly. MLS reports lectures, advisory boards, and/or PI in clinical trials for Pfizer, Teva Pharmaceuticals, Novartis, Lundbeck, AbbVie, and Eli Lilly. CT reports personal fees for the participation in advisory boards or symposia for AbbVie, Dompé, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals; she reports institutional fees for conducting clinical trials for AbbVie, Dompé, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva Pharmaceuticals; she received funding for research projects from the European Commission, the Italian Ministry of Health, the Migraine Research Foundation, and the Italian Multiple Sclerosis Foundation.

The 2030 Agenda for Sustainable Development sets out, through 17 Sustainable Development Goals (SDGs), a path for the prosperity of people and the planet. SDG 3 in particular aims to ensure healthy lives and promote well-being for all at all ages and includes several targets to enhance health. This review presents a "headache-tailored" perspective on how to achieve SDG 3 by focusing on six specific actions: targeting chronic headaches; reducing the overuse of acute pain-relieving medications; promoting the education of healthcare professionals; granting access to medication in low- and middle-income countries (LMIC); implementing training and educational opportunities for healthcare professionals in low and middle income countries; building a global alliance against headache disorders. Addressing the burden of headache disorders directly impacts on populations' health, as well as on the possibility to improve the productivity of people aged below 50, women in particular. Our analysis pointed out several elements, and included: moving forward from frequency-based parameters to define headache severity; recognizing and managing comorbid diseases and risk factors; implementing a disease management multi-modal management model that incorporates pharmacological and non-pharmacological treatments; early recognizing and managing the overuse of acute pain-relieving medications; promoting undergraduate, postgraduate, and continuing medical education of healthcare professionals with specific training on headache; and promoting a culture that favors the recognition of headaches as diseases with a neurobiological basis, where this is not yet recognized. Making headache care more sustainable is an achievable objective, which will require multi-stakeholder collaborations across all sectors of society, both health-related and not health-related. Robust investments will be needed; however, considering the high prevalence of headache disorders and the associated disability, these investments will surely improve multiple health outcomes and lift development and well-being globally., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

A recessive Short Tandem Repeat expansion in RFC1 has been found to be associated with cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), and to be a frequent cause of late onset ataxia and sensory neuropathy. The usual procedure for sizing these expansions is based on Southern Blotting (SB), a time-consuming and a relatively imprecise technique. In this paper, we compare SB with Optical Genome Mapping (OGM), a method for detecting Structural Variants (SVs) based on the measurement of distances between fluorescently labelled probes, for the diagnosis of RFC1 CANVAS and disease spectrum. The two methods are applied to 17 CANVAS patients' blood samples and resulting sizes compared, showing a good agreement. Further, long-read sequencing is used for two patients to investigate the agreement of sizes with either SB or OGM. Our study concludes that OGM represents a viable alternative to SB, allowing for a simpler technique, a more precise sizing of the expansion and ability to expand analysis of SV in the entire genome as opposed to SB which is a locus specific method.

Background: To date, there is still a lack of consensus for identifying the ideal candidate for cognitive telerehabilitation (TR). The main goal of the present study is to identify the factors associated to the preference for either TR or in-person cognitive training (CT) programs in older adults at risk of dementia or with early cognitive impairment., Methods: A sample of 56 participants with subjective cognitive decline or neurocognitive disorders eligible for CT were enrolled at the Dementia Research Center and Neurorehabilitation Unit of IRCCS Mondino Foundation. All individuals underwent a baseline assessment to capture their complete profile, including cognitive reserve and lifestyle habits, sociodemographic characteristics, cognitive functioning, and mental health. Patients were then asked their preference for TR or in-person CT, before being randomized to either treatment as per protocol procedures. Statistical analyses included explorative descriptive approach, logistic regression, and non-parametric models to explore the overall contribution of each variable., Results: The two (TR and in-person) preference groups were similar for cognitive functioning and mental health status. Socio-demographic and lifestyle profiles seem to be the most important factors to influence the preference in terms of the area under the curve (AUC) of the models. The two preference groups differed in terms of socio-demographic characteristics (e.g., level of technological skills, age, and distance from the clinic). Furthermore, participants who selected the TR modality of CT had significantly higher levels of cognitive reserve and adopted more protective lifestyle habits (e.g., regular physical activity, Mediterranean diet) when compared to those who preferred in-person CT., Discussion: These findings highlight that the preference to receive CT delivered by TR or in person is a complex issue and is influenced by a variety of factors, mostly related to lifestyle habits and sociodemographic characteristics. Availability of profiles of patients that may be more attracted to one or the other modality of TR may help promote shared decision-making to enhance patient experience and outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Bernini, Ballante, Fassio, Panzarasa, Quaglini, Riccietti, Costa, Cappa, Tassorelli, Vecchi and Bottiroli.)

Background: Migraine is a highly prevalent primary headache disorder and a leading cause of disability. Difficulties in access to care during diagnostic and therapeutic journey contribute to the disease burden. Several target-specific drugs have reached the market in the past four years and have modified the treatment paradigm in migraine. The aim of this study is to provide an updated snapshot of the pathways and hurdles to care for migraine in different European countries by directly asking patients., Methods: In 2021 the European Migraine and Headache Alliance proposed a 39-item questionnaire that was administered online to an adult migraine population in European countries. Questions were focused on socio-demographic and migraine data, access to diagnosis and treatment, disease-related burden and the main channel for disease information., Results: A total of 3169 questionnaires were returned from 10 European countries. Responders were predominantly females, age range 25-59 years, with a migraine history longer than 10 years in 82% of cases, and with at least 8 headache days per month in 57% of cases. Respondents reported limitations in social, working and personal life during both the ictal and interictal phase. The activities mostly impaired during the attacks were driving (55%), cooking or eating (42%), taking care of family/childcare (40%) and getting medicines at the pharmacy (40%). The most frequently reported unmet need was the long delay between the first visit and migraine diagnosis: 34% of respondents had to see ≥ 4 specialists before being correctly diagnosed, and between the diagnosis and treatment prescription: > 5 years in 40% of cases. The most relevant needs in terms of quality of life were the desire for a lower migraine frequency, an effective treatment and a greater involvement in society., Conclusions: Data from the present survey point to the existence and persistence of multiple hurdles that result in significant limitations to access to care and to the patients' social life. A close cooperation between decision makers, healthcare workers and patients is needed to overcome these barriers., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Background: Chronic headache (CH) is a condition that includes different subtypes of headaches and that can impair different life domains. Personality traits can play a relevant role both in the development and in coping with this medical condition. The first aim of the present study is to realize a systematic review of the personality traits associated with CH compared to healthy controls; the second objective is to carry out a quantitative meta-analysis with the studies using the same instrument to assess personality traits., Method: The literature search encompassed articles published from 1988 until December 2022 on the major databases in the field of health and social sciences: PubMed, Scopus, PsychInfo, and Web of Science., Results: Thirteen studies were included in the systematic review, but only three studies were deeply explored in a meta-analysis since the only ones used a common instrument for personality assessment (Minnesota Multiphasic Personality Inventory). According to the meta-analysis, different subtypes of CH patients scored higher than healthy controls on Hypochondriasis and Hysteria Scales. The systematic review showed higher levels of depressive and anxious personality dimensions and pain catastrophizing in CH compared to healthy controls. Moreover, frequent-chronic forms and medication-overuse headache were the most symptomatic and frail categories showing higher levels of dysfunctional personality traits and psychopathological symptoms., Conclusions: These results seem to confirm a "neurotic profile" in patients suffering from CH. The identification of the main personality traits involved in the onset and maintenance of headache disorders represents an important objective for developing psychological interventions., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2023 Sara Bottiroli et al.)

Background: Matters of workplace harassment are an important issue. This issue needs to be recognized and studied to prevent occurrences. These important sensitive areas of effective workplace management are increasingly gaining more interest. We aimed to identify the prevalence of workplace sexual, verbal and physical harassment among headache professionals., Methods: We adopted a cross‑sectional exploratory survey approach with quantitative design. The survey was distributed electronically among headache healthcare and research professionals globally through the International Headache Society (IHS)., Results: Data were obtained from 579 respondents (55.3%; 320/579 women). A large percentage of respondents (46.6%; 270/579) had experienced harassment; specifically, 16.1% (93/578) reported sexual harassment, 40.4% (234/579) verbal harassment and 5.5% (32/579) physical harassment. Women were almost seven times more likely to experience sexual harassment compared to men (odds ratio = 6.8; 95% confidence interval = 3.5-13.2). Although women did also more frequently report other types of harassment, this was not statistically significant (odds ratio = 1.4; 95% confidence interval = 1.0-2.0)., Conclusions: Lifetime exposure to workplace harassment is prevalent among headache professionals, especially in women. The present study uncovers a widespread issue and calls for strategies to be implemented for building a healthy and safe workplace environment.

The quality of clinical trials is essential to advance treatment, inform regulatory decisions and meta-analysis. With the increased incidence of idiopathic intracranial hypertension and the emergence of clinical trials for novel therapies in this condition, the International Headache Society Guidelines for Controlled Clinical Trials in Idiopathic Intracranial Hypertension aims to establish guidelines for designing state-of-the-art controlled clinical trials for idiopathic intracranial hypertension.

Background: The Cluster Headache Impact Questionnaire (CHIQ) is a specific and easy-to-use questionnaire to assess the current impact of cluster headache (CH). The aim of this study was to validate the Italian version of the CHIQ., Methods: We included patients diagnosed with episodic CH (eCH) or chronic CH (cCH) according to the ICHD-3 criteria and included in the "Italian Headache Registry" (RICe). The questionnaire was administered to patients through an electronic form in two sessions: at first visit for validation, and after 7 days for test-retest reliability. For internal consistency, Cronbach's alpha was calculated. Convergent validity of the CHIQ with CH features and the results of questionnaires assessing anxiety, depression, stress, and quality of life was evaluated using Spearman's correlation coefficient., Results: We included 181 patients subdivided in 96 patients with active eCH, 14 with cCH, and 71 with eCH in remission. The 110 patients with either active eCH or cCH were included in the validation cohort; only 24 patients with CH were characterized by a stable attack frequency after 7 days, and were included in the test-retest cohort. Internal consistency of the CHIQ was good with a Cronbach alpha value of 0.891. The CHIQ score showed a significant positive correlation with anxiety, depression, and stress scores, while showing a significant negative correlation with quality-of-life scale scores., Conclusion: Our data show the validity of the Italian version of the CHIQ, which represents a suitable tool for evaluating the social and psychological impact of CH in clinical practice and research., (© 2023. The Author(s).)

Primary Progressive Aphasia (PPA) is a syndrome due to different neurodegenerative disorders selectively disrupting language functions. PPA specialist care is underdeveloped. There are very few specialists (neurologists, psychiatrists, neuropsychologists, and speech therapists) and few hospital- or community-based services dedicated to the diagnosis and continuing care of people with PPA. Currently, healthcare systems struggle to provide adequate coverage of care that is too often fragmented, uncoordinated, and unresponsive to the needs of people with PPA and their families. Recently, attention has been gained by non-invasive brain stimulation techniques that allow a personalized treatment approach, such as transcranial Direct Current Stimulation (tDCS). The MAINSTREAM trial looks forward to introducing and evaluating therapeutic innovations such as tDCS coupled with language therapy in rehabilitation settings. A Multimodal Approach for Clinical Diagnosis and Treatment of Primary Progressive Aphasia, MAINSTREAM (ID: 3430931) was registered in the clinicaltrials.gov database (identifier: NCT05730023) on 15 February 2023.

Increased anandamide levels via fatty acid amide hydrolase (FAAH) inhibition can decrease the pronociceptive responses and inflammatory mediators in animal models of migraine. Here, we profile the pharmacological activity of the FAAH inhibitor JZP327A, a chiral 1,3,4-oxadiazol-2(3H)-one compound, in the mediation of spontaneous and nocifensive behaviour in the animal models of migraine based on nitroglycerin (NTG) administration. JZP327A (0.5 mg/kg, i.p.) or vehicle was administered to male rats 3 h after NTG (10 mg/kg, i.p.) or NTG vehicle injection. The rats were then exposed to the open field test and an orofacial formalin test 1 h later. The levels of endocannabinoids and lipid-related substances, and the expression of pain and inflammatory mediators were evaluated in cranial tissues and serum. The findings show that JZP327A did not affect NTG-induced changes in the spontaneous behaviour of rats, while it inhibited NTG-induced hyperalgesia at the orofacial formalin test. Furthermore, JZP327A dramatically decreased the gene expression of calcitonin gene-related peptide ( CGRP ) , tumor necrosis factor alpha ( TNF-alpha ) and interleukin 6 ( IL-6 ) in the trigeminal ganglia and medulla-pons, while it did not change endocannabinoids or lipids levels nor CGRP serum levels in the same tissues. These data suggest an anti-hyperalgesic role for JZP327A in the NTG model, which is mediated by the inhibition of the inflammatory cascade of events. This activity does not seem mediated by a change in the levels of endocannabinoids and lipid amides.

The global burden of neurological disorders is substantial and increasing, especially in low-resource settings. The current increased global interest in brain health and its impact on population wellbeing and economic growth, highlighted in the World Health Organization's new Intersectoral Global Action Plan on Epilepsy and other Neurological Disorders 2022-2031, presents an opportunity to rethink the delivery of neurological services. In this Perspective, we highlight the global burden of neurological disorders and propose pragmatic solutions to enhance neurological health, with an emphasis on building global synergies and fostering a 'neurological revolution' across four key pillars - surveillance, prevention, acute care and rehabilitation - termed the neurological quadrangle. Innovative strategies for achieving this transformation include the recognition and promotion of holistic, spiritual and planetary health. These strategies can be deployed through co-design and co-implementation to create equitable and inclusive access to services for the promotion, protection and recovery of neurological health in all human populations across the life course., (© 2023. Springer Nature Limited.)

OnabotulinumtoxinA (BonT-A) reduces migraine frequency in a considerable portion of patients with migraine. So far, predictive characteristics of response are lacking. Here, we applied machine learning (ML) algorithms to identify clinical characteristics able to predict treatment response. We collected demographic and clinical data of patients with chronic migraine (CM) or high-frequency episodic migraine (HFEM) treated with BoNT-A at our clinic in the last 5 years. Patients received BoNT-A according to the PREEMPT (Phase III Research Evaluating Migraine Prophylaxis Therapy) paradigm and were classified according to the monthly migraine days reduction in the 12 weeks after the fourth BoNT-A cycle, as compared to baseline. Data were used as input features to run ML algorithms. Of the 212 patients enrolled, 35 qualified as excellent responders to BoNT-A administration and 38 as nonresponders. None of the anamnestic characteristics were able to discriminate responders from nonresponders in the CM group. Nevertheless, a pattern of four features (age at onset of migraine, opioid use, anxiety subscore at the hospital anxiety and depression scale (HADS-a) and Migraine Disability Assessment (MIDAS) score correctly predicted response in HFEM. Our findings suggest that routine anamnestic features acquired in real-life settings cannot accurately predict BoNT-A response in migraine and call for a more complex modality of patient profiling.

The aim of this study was to assess the ability of multiscale sample entropy (MSE), refined composite multiscale entropy (RCMSE), and complexity index (CI) to characterize gait complexity through trunk acceleration patterns in subjects with Parkinson's disease (swPD) and healthy subjects, regardless of age or gait speed. The trunk acceleration patterns of 51 swPD and 50 healthy subjects (HS) were acquired using a lumbar-mounted magneto-inertial measurement unit during their walking. MSE, RCMSE, and CI were calculated on 2000 data points, using scale factors ( τ ) 1-6. Differences between swPD and HS were calculated at each τ , and the area under the receiver operating characteristics, optimal cutoff points, post-test probabilities, and diagnostic odds ratios were calculated. MSE, RCMSE, and CIs showed to differentiate swPD from HS. MSE in the anteroposterior direction at τ 4 and τ 5, and MSE in the ML direction at τ 4 showed to characterize the gait disorders of swPD with the best trade-off between positive and negative posttest probabilities and correlated with the motor disability, pelvic kinematics, and stance phase. Using a time series of 2000 data points, a scale factor of 4 or 5 in the MSE procedure can yield the best trade-off in terms of post-test probabilities when compared to other scale factors for detecting gait variability and complexity in swPD.

Cannabidiol (CBD) is the main pharmacologically active phytocannabinoid. CBD exerts an analgesic effect in several pain models, does not have side effects and has low toxicity. The data about CBD mechanisms of action in pain and its therapeutic potential in this area are limited. Here, we tested CBD effects in animal models specific for migraine. We assayed CBD distribution in plasma and in cranial areas related to migraine pain in male Sprague Dawley rats treated chronically (5 days). Successively, we tested CBD activity on the behavioral and biochemical effects induced in the acute and the chronic migraine animal models by nitroglycerin (NTG) administration. In the acute migraine model, rats received CBD (15 mg or 30 mg/kg, i.p) 3 h after NTG (10 mg/kg i.p.) or vehicle injection. In the chronic migraine model, rats were treated with CBD and NTG every other day over nine days with the following doses: CBD 30 mg/kg i.p., NTG 10 mg/kg i.p. We evaluated behavioral parameters with the open field and the orofacial formalin tests. We explored the fatty acid amide hydrolase gene expression, cytokines mRNA and protein levels in selected brain areas and CGRP serum level. CBD levels in the meninges, trigeminal ganglia, cervical spinal cord, medulla pons, and plasma were higher 1 h after the last treatment than after 24 h, suggesting that CBD penetrates but does not accumulate in these tissues. In the acute model, CBD significantly reduced NTG-induced trigeminal hyperalgesia and CGRP and cytokine mRNA levels in peripheral and central sites. In the chronic model, CBD caused a significant decrease in NTG-induced IL-6 protein levels in the medulla-pons, and trigeminal ganglion. It also reduced CGRP serum levels. By contrast, CBD did not modulate TNF-alpha protein levels and fatty acid amide hydrolase (FAAH) gene expression in any of investigated areas. In both experimental conditions, there was no modulation of anxiety, motor/exploratory behavior, or grooming. These findings show that CBD reaches brain areas involved in migraine pain after systemic administration. They also show for the first time that CBD modulates migraine-related nociceptive transmission, likely via a complex signaling mechanism involving different pathways., (© 2023. The Author(s).)

Background: Recent experience in designing and running clinical trials on new medications for the prevention of migraine in children and adolescents highlighted the need for revision of the 1st edition of the International Headache Society Guidelines for clinical trials of preventive treatment of migraine in children and adolescents which were published in 2019., Methods: The authors of the 1st edition of the guidelines formed an informal focus group with aims of appraising the performance of the guidelines, clarifying any ambiguity and providing improvements, where needed, based on personal experience and expert analysis., Results: This review and the following update were able to address issues related to the classification of migraine, the duration of migraine attacks, the age groups of children and adolescents, the use of electronic diaries, the assessment of outcome measures, the need for an interim analysis and the issues related to placebo response., Conclusions: This update provides necessary clarifications of the guidelines in order to enable better design and running of future clinical trials for the preventive treatment of migraine in children and adolescents.

Background and Objective: OnabotulinumtoxinA (BoNTA) is a relatively safe and effective treatment for chronic migraine. The local mode of action of BoNTA favors the combination of oral treatments with systemic action. However, little is known about the possible interactions with other preventive treatments. The objective of the study was to describe the use of oral preventive treatments in patients with chronic migraine treated with BoNTA in routine clinical care and discuss the tolerability and efficacy according to the presence or absence of concomitant oral treatments., Methods: In this multicenter, observational, retrospective, cohort study, we collected data from patients with chronic migraine receiving prophylactic treatment with BoNTA. Patients were eligible if aged ≥18 years, diagnosed with chronic migraine according to the International Classification of Headache Disorders, Third Edition criteria, and treated with BoNTA according to the PREEMPT paradigm. We documented the proportion of patients with at least one concomitant treatment prescribed specifically for migraine (CT+M) and their side effects during four BoNTA treatment cycles. Additionally, we collected monthly headache days and monthly acute medication days from the patients' headache diaries. Patients with CT+M were compared to those without concomitant treatment (CT-) using a nonparametric approach., Results: Our cohort included 181 patients taking BoNTA, of whom 77 (42.5%) received a CT+M. The most frequently prescribed concomitant treatments were antidepressants and antihypertensive drugs. Side effects in the CT+M group occurred in 14 patients (18.2%). Only in three of them (3.9%), the side effects had a significant interference with the patient's functioning (all in topiramate 200-mg/day users). Both CT+M and CT- groups had a significant reduction in monthly headache days of respectively - 6 (95% confidence interval - 9, - 3; p < 0.001; w = 0.200) during cycle 4 compared with baseline versus - 9 (95% confidence interval - 13, -6; p < 0.001; w = 0.469). However, the reduction in monthly headache days was significantly smaller in patients with CT+M after the fourth treatment cycle compared with patients with CT- (p = 0.004)., Conclusions: Prescription of oral concomitant preventive treatment is common in patients with chronic migraine receiving BoNTA. We did not identify any unexpected safety or tolerability issues in patients receiving BoNTA and a CT+M. However, patients with a CT+M experienced a smaller reduction in monthly headache days when compared with those with CT-, which might be associated with a higher resistance to treatment in that subgroup of patients., (© 2023. The Author(s).)

This study investigated the short-term impact and the retention of a dementia care intervention for healthcare staff working in an Italian acute hospital setting. Additionally, we identified the predictors of improvement across the intervention., Sixty-two healthcare staff from an Italian public hospital participated in a dementia care intervention consisting of 5 modules delivered in a 5-hour training program focusing on dementia management, knowledge, and care. A pre-test/post-test and six-months follow-up design was used to evaluate participants' changes in knowledge, attitudes, and confidence in dementia., The intervention significantly improved healthcare staff's dementia knowledge and confidence immediately after the end of the intervention. No significant changes were observed from post-test to follow-up, indicating retention of these outcomes over six months. Regarding attitude to dementia, we found an immediate improvement only in the Recognition of Personhood scale. Looking at the predictors of improvement, healthcare staff with lower levels of knowledge, attitudes, and confidence in dementia at pre-test were those who improved more following the intervention., These findings provide further evidence that dementia care interventions are suitable initiatives to promote knowledge and skills required to manage the needs of people with dementia in an acute hospital setting.

Background: Social cognition refers to all mental operations to decipher information needed in social interactions. Here we aimed to outline the socio-cognitive profile of Chronic Migraine with Medication Overuse (CM + MO), given they are recognized to be at risk of socio-cognitive difficulties. Given the multidimensionality of this construct, we considered: (1) socio-cognitive abilities, (2) socio-cognitive beliefs, (3) alexithymia and autism traits, and (4) social relationships., Methods: Seventy-one patients suffering from CM + MO, 61 from episodic migraine (EM), and 80 healthy controls (HC) were assessed with a comprehensive battery: (1) the Faux Pas test (FP), the Strange Stories task (SS), the Reading Mind in the Eyes test (RMET), (2) the Tromsø Social Intelligence Scale, (3) the Toronto Alexithymia Scale, the Autism Spectrum Quotient, (4) the Lubben Social Network Scale, the Friendship Scale., Results: CM + MO: (1) performed similar to EM but worse than HC in the FP and SS, while they were worse than EM and HC in the RMET; (2) were similar to EM and HC in social intelligence; (3) had more alexithymic/autistic traits than EM and HC; (4) reported higher levels of contact with their family members but felt little support from the people around them than HC., Conclusions: CM + MO results characterized by a profile of compromised socio-cognitive abilities that affects different dimensions. These findings may have a relevant role in multiple fields related to chronic headache: from the assessment to the management., (© 2023. The Author(s).)

Background: People with chronic neurological diseases, such as Parkinson's Disease (PD) and Multiple Sclerosis (MS), often present postural disorders and a high risk of falling. When difficulties in achieving outpatient rehabilitation services occur, a solution to guarantee the continuity of care may be telerehabilitation. This study intends to expand the scope of our previously published research on the impact of telerehabilitation on quality of life in an MS sample, testing the impact of this type of intervention in a larger sample of neurological patients also including PD individuals on postural balance., Methods: We included 60 participants with MS and 72 with PD. All enrolled subjects were randomized into two groups: 65 in the intervention group and 67 in the control group. Both treatments lasted 30-40 sessions (5 days/week, 6-8 weeks). Motor, cognitive, and participation outcomes were registered before and after the treatments., Results: All participants improved the outcomes at the end of the treatments. The study's primary outcome (Mini-BESTest) registered a greater significant improvement in the telerehabilitation group than in the control group., Conclusions: Our results demonstrated that non-immersive virtual reality telerehabilitation is well tolerated and positively affects static and dynamic balance and gait in people with PD and MS.

Electrokinesiographic study of swallowing (EKSS) can be useful for the assessment of patients with suspected or overt neurogenic dysphagia. EKSS consists of multichannel recording of the electromyographic (EMG) activity of the suprahyoid/submental muscle complex (SHEMG), the EMG activity of the cricopharyngeal muscle (CPEMG), and the laryngopharyngeal mechanogram (LPM). The LPM is an expression of the mechanical changes that the laryngopharyngeal structures undergo during the pharyngeal phase of swallowing. This method allows detailed evaluation of the magnitude, duration and temporal relations of the different events that characterize oropharyngeal swallowing, and thus in-depth exploration both of physiological deglutition mechanisms and of pathophysiological features of swallowing in neurogenic dysphagia. Furthermore, EKSS can guide dysphagia treatment strategies, allowing identification of optimal solutions for single patients. For instance, CPEMG recording can identify incomplete or absent relaxation of the upper esophageal sphincter during the pharyngeal phase of swallowing, thus suggesting a therapeutic approach based on botulinum toxin injection into the cricopharyngeal muscle. More recently, the 'shape' of SHEMG and the reproducibility of both SHEMG and LPM over repeated swallowing acts have been implemented as novel electrokinesiographic parameters. These measures could be valuable for straightforward non-invasive investigation of dysphagia severity and response to dysphagia treatment in clinical practice., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In recent years, numerous efforts have been made to identify reliable biomarkers useful in migraine diagnosis and progression or associated with the response to a specific treatment. The purpose of this review is to summarize the alleged diagnostic and therapeutic migraine biomarkers found in biofluids and to discuss their role in the pathogenesis of the disease. We included the most informative data from clinical or preclinical studies, with a particular emphasis on calcitonin gene-related peptide (CGRP), cytokines, endocannabinoids, and other biomolecules, the majority of which are related to the inflammatory aspects and mechanisms of migraine, as well as other actors that play a role in the disease. The potential issues affecting biomarker analysis are also discussed, such as how to deal with bias and confounding data. CGRP and other biological factors associated with the trigeminovascular system may offer intriguing and novel precision medicine opportunities, although the biological stability of the samples used, as well as the effects of the confounding role of age, gender, diet, and metabolic factors should be considered.

Background: We performed a random-effects network meta-analysis to study the efficacy and safety of newly developed drugs for the acute treatment of migraine attacks., Methods: MEDLINE via PubMed, Embase and The Cochrane Register of Controlled Trials were searched from inception to 11 February 2022. Phase 3 randomized controlled trials examining all formulations of lasmiditan, rimegepant and ubrogepant for the acute treatment of adults with migraine, were included. Data were extracted following the PRISMA guidelines., Results: Seven studies (SAMURAI, SPARTAN, CENTURION, Study 302, Study 303, ACHIEVE I and II) involving n  = 12,859 patients were included. All treatments were superior in efficacy to placebo. Lasmiditan 200 mg showed the highest two-hour pain freedom, while two-hour freedom from most bothersome symptom was equally achieved by the higher doses of lasmiditan (100 and 200 mg), rimegepant and the higher doses of ubrogepant (50 and 100 mg). The odds of treatment-emergent adverse events were greatest with all doses of lasmiditan., Conclusion: Lasmiditan 200 mg was the most effective intervention in the treatment of migraine attacks, although it was associated with high degrees of dizziness, nausea and somnolence. Rimegepant showed slightly lower, but similar efficacy rates to lasmiditan. Ubrogepant had overall the best tolerability profile. These conclusions are limited by the absence of head-to-head comparisons, limitations of individual trials and of the meta-analysis methodology itself. PROSPERO trial registration: CRD42022308224.

Importance: Trigeminal autonomic cephalalgias (TACs) comprise a unique collection of primary headache disorders characterized by moderate or severe unilateral pain, localized in in the area of distribution of the first branch of the trigeminal nerve, accompanied by cranial autonomic symptoms and signs. Most TACs are rare diseases, which hampers the possibility of performing randomized clinical trials and large studies. Therefore, knowledge of treatment efficacy must be based only on observational studies, rare disease registries, and case reports, where real-world data and evidence play an important role in health care decisions., Observations: Chronic cluster headache is the most common of these disorders, and the literature offers some evidence from randomized clinical trials to support the use of pharmacologic and neurostimulation treatments. Galcanezumab, a monoclonal antibody targeting the calcitonin gene-related peptide, was not effective at 3 months in a randomized clinical trial but showed efficacy at 12 months in a large case series. For the other TACs (ie, paroxysmal hemicrania, hemicrania continua, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms), only case reports and case series are available to guide physicians in everyday management., Conclusions and Relevance: The accumulation of epidemiologic, pathophysiologic, natural history knowledge, and data from case series and small controlled trials, especially over the past 20 years from investigators around the world, has added to the previously limited evidence and has helped advance and inform the treatment approach to rare TACs, which can be extremely challenging for clinicians.

Introduction: Migraine is a highly prevalent and disabling neurological disease. Excessive use of acute medications can lead to medication-overuse headache (MOH), occurring when a patient experiences an increasing number of headache and migraine days, despite taking greater amounts of acute medication. To treat MOH, a preventive migraine treatment and/or withdrawal of the overused medication(s) are advised. Brief Educational Intervention (BEI) has been shown to be an effective tool with promising results for MOH. Here, we report the design of a clinical trial that aims to evaluate the efficacy of eptinezumab, an anti-calcitonin gene-related peptide preventive migraine treatment, as an add-on to BEI for treatment of MOH in those with chronic migraine., Methods and Analysis: RESOLUTION will be a phase 4, multi-national, randomized, double-blind, placebo-controlled study. This study will enroll approximately 570 participants with dual diagnoses of chronic migraine and MOH. Eligible patients will be randomly allocated to one of two treatment groups, BEI and eptinezumab (100 mg; n = 285) or BEI and placebo ( n = 285), in a 1:1 ratio. The primary endpoint is the change from baseline in monthly migraine days over weeks 1-4. Secondary and exploratory endpoints will assess monthly migraine days over weeks 1-12, MOH remission, transition from chronic to episodic migraine, health-related quality of life, work productivity, and the safety and tolerability of eptinezumab in this patient population., Ethics and Dissemination: This study will be conducted in accordance with good clinical practice. All patients will be fully informed about the study, including the risks and benefits of participation, and all participants will provide informed consent for participation in the trial and dissemination of results., Competing Interests: RJ has given lectures for Pfizer, Berlin-Chemie, Norspan, Merck, Autonomic Technologies, Teva, Allergan/AbbVie, Lundbeck, and Novartis and she is or has been a principal investigator on clinical trials sponsored by Eli Lilly, Lundbeck, and Autonomic Technologies. HS has received personal fees from Novartis, Lilly, Allergan/AbbVie, Teva, and Lundbeck and research support from Novartis, has served on advisory boards for Teva and Lundbeck, and is affiliated with BMJ Open as a reviewer. CT has received funding for participation in Advisory Boards or for scientific presentations from Allergan/AbbVie, Eli Lilly, Lundbeck, Novartis, and Teva and is or has been a principal investigator in clinical trials sponsored by Allergan, Eli Lilly, Lundbeck, Novartis, and Teva. GT is a board member for the Dutch Headache Society and the CGRP Education and Research Forum and is an advisory member for the Dutch Headache Alliance; she has received personal fees from Consultancy: Novartis, Teva, Allergan, Lilly, and Lundbeck, received research support from the Dutch Brain Foundation, Dutch Heart Foundation, Dutch Research Council, IRRF, and Dioraphte (all to institution), has a pending patent for an eDiary collaboration with Interactive Studios, is involved with the clinical trial WHATstudy on the effect of hormonal treatment in migraine, is a National Primary Investigator in the ALLEVIATE and CHRONICLE studies by Lundbeck, and is also a presenter for satellite symposia/webinars with Springer Media (Mednet)/Ashfield MedComms. LC has received grants from the Danish Health Authority. AM is a current employee of Lundbeck. OØ was previously an employee of Lundbeck and is now employed by Biogen. RL has been a consultant, advisory board member, and/or has received honoraria from Lundbeck Seattle BioPharmaceuticals, Allergan, American Academy of Neurology, American Headache Society, Amgen, Biohaven Pharmaceuticals, BioVision, Boston Scientific, Dr. Reddy's Laboratories, electroCore Medical, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Pernix, Pfizer, Supernus, Teva Pharmaceuticals, Trigemina, Vector, and Vedanta, received compensation from eNeura and Biohaven Pharmaceuticals, has stock or stock options in Biohaven Pharmaceuticals and Manistee, and has received research support from Amgen, Migraine Research Foundation, and National Headache Foundation. ST reports grants for research (no personal compensation) from Allergan/AbbVie, Amgen, Eli Lilly, Lundbeck, Neurolief, Novartis, Satsuma, and Zosano, is a consultant and/or on advisory boards (honoraria) for Aeon, Allergan/AbbVie, Alphasights, Amgen, Aruene, Atheneum, Axsome Therapeutics, Becker Pharmaceutical Consulting, BioDelivery Sciences International, Biohaven, ClearView Healthcare Partners, Click Therapeutics, Collegium, CoolTech, CRG, Decision Resources, Defined Health, DRG, Eli Lilly, ExpertConnect, FCB Health, Fenix, GLG, Guidepoint Global, Health Advances, Health Science Communications, HMP Communications, Impel, InteractiveForums, Keyquest, Krog and Partners, Lundbeck, M3 Global Research, Magnolia Innovation, MJH Holdings, Neurofront Therapeutics, Neurolief, Novartis, P Value Communications, Pain Insights Inc, Palion Medical, Pulmatrix, Putnam Associates, SAI MedPartners, Satsuma, Slingshot Insights, Spherix Global Insights, Strategy Inc, System Analytic, Taylor and Francis, Teva, Theranica, Tremeau, Unity HA, XOC, and Zosano, and reports salary from Dartmouth-Hitchcock Medical Center and Thomas Jefferson University, and CME honoraria from the American Academy of Neurology, American Headache Society, Catamount Medical Education, Diamond Headache Clinic, Forefront Collaborative, Haymarket Medical Education, Peerview, Medical Education Speakers Network, Migraine Association of Ireland, National Association for Continuing Education, North American Center for CME, The Ohio State University, Physicians' Education Resource, PlatformQ Education, Primed, Vindico Medical Education, and WebMD/Medscape. AB has served on advisory boards for Allergan, AbbVie, Aeon, Alder, Amgen, Axsome, Biohaven, Impel, Lundbeck, Lilly, Novartis, Revance, Teva, Theranica, and Zosano; has received funding for speaking from Allergan, AbbVie, Amgen, Biohaven, Lundbeck, Lilly, and Teva; has served as a consultant for Allergan, AbbVie, Alder, Amgen, Biohaven, Lilly, Lundbeck, Novartis, Teva, and Theranica, received grant support from Allergan and Amgen, and has been a contributing author for Allergan, AbbVie, Amgen, Novartis, Teva, Lilly, and Biohaven. CL has participated on an advisory board and received payment for lectures arranged by AbbVie Pharma AS, Lundbeck, Novartis AS, and Roche AS, Norway and he has received research sponsorship from AbbVie Pharma, and is a regular reviewer with BMJ., (Copyright © 2023 Jensen, Schytz, Tassorelli, Terwindt, Carlsen, Mittoux, Østerberg, Lipton, Tepper, Blumenfeld and Lundqvist.)

Background: Telerehabilitation has enabled a broader application of cognitive rehabilitation programs. We have recently developed HomeCoRe, a system for supporting cognitive intervention remotely with the assistance of a family member. The main goal of the present study was to determine usability and user experience of HomeCoRe in individuals at risk of dementia and in their family members. The association between subjects' technological skills and main outcome measures was evaluated as well., Methods: Fourteen individuals with subjective cognitive decline (SCD) or mild neurocognitive disorder (mNCD) were recruited to participate in this pilot study. All participants received a touch-screen laptop implemented with the HomeCoRe software. The intervention consisted of 18 sessions and included a patient-tailored adaptive protocol of cognitive exercises. Usability was assessed in terms of treatment adherence and participants' performance across sessions; user experience via self-reported questionnaires and a descriptive diary., Results: Usability and user experience were overall satisfactory and suggested usability, pleasantness, and high motivation while using HomeCoRe. Technological skills correlated only with the perceived ability to start and/or perform exercises autonomously., Discussion: These results, although preliminary, suggest that the usability and user experience of HomeCoRe are satisfactory and independent of technological skills. These findings encourage wider and more systematic use of HomeCoRe to overcome the current limitations of in-person cognitive rehabilitation programs and to reach more individuals at risk of dementia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bernini, Panzarasa, Quaglini, Costa, Picascia, Cappa, Cerami, Tassorelli, Vecchi and Bottiroli.)

The present study aimed to identify clusters of cognitive profiles as well as to explore the effects of these clusters on demographic/individual characteristics and on improvements after a computer-based cognitive training (CCT) in early cognitive impairment. Fifty-seven subjects underwent to an adaptive CCT for 3 weeks (4 individual face-to-face sessions/week of 45 min) and were evaluated at baseline (T0), post-intervention (T1), and after 6 (T2) and 12 (T3) months. Clusters of cognitive profiles were explored with k-means analysis. The analysis revealed two clusters, which were composed by 27 and 30 patients characterized by lower (Cluster 1) and higher (Cluster 2) cognitive functioning. At T1, cognitive performance improved in both groups, but Cluster 1 gained more benefits in global cognitive functioning than Cluster 2. However, at T3, Cluster 2 remained stable in its clinical condition, whereas Cluster 1 showed a pronounced worsening. In conclusion, Cluster 1 profile was associated with a more marked but also short-lasting responsiveness to CCT, whereas patients fitting with Cluster 2 characteristics seemed to obtain more CCT benefits in terms of stability or even delay of cognitive/functional decline. These findings may have relevant implications in informing the timing and modality of delivery of CCT., (© 2023. The Author(s).)

Medication overuse headache (MOH) is a secondary headache disorder attributed to overuse of acute headache medications by a person with an underlying headache disorder, usually migraine or tension-type headache. MOH is common among individuals with 15 or more headache days per month. Although MOH is associated with substantial disability and reductions in quality of life, this condition is often under-recognized. As MOH is both preventable and treatable, it warrants greater attention and awareness. The diagnosis of MOH is based on the history and an unremarkable neurological examination, and is made according to the diagnostic criteria of the International Classification of Headache Disorders third edition (ICHD-3). Pathophysiological mechanisms of MOH include altered descending pain modulation, central sensitization and biobehavioural factors. Treatment of MOH includes the use of headache preventive therapies, but essential to success is eliminating the cause, by reducing the frequency of use of acute headache medication, and perhaps withdrawing the overused medication altogether. Appropriate treatment is usually highly effective, leading to reduced headache burden and acute medication consumption., (© 2023. Springer Nature Limited.)

Background: Vertebral arthrodesis for degenerative pathology of the lumbar spine still remains burdened by clinical problems with significant negative results. The introduction of the sagittal balance assessment with the evaluation of the meaning of pelvic parameters and spinopelvic (PI-LL) mismatch offered new evaluation criteria for this widespread pathology, but there is a lack of consistent evidence on long-term outcome., Methods: The authors performed an extensive systematic review of literature, with the aim to identify all potentially relevant studies about the role and usefulness of the restoration or the assessment of Sagittal balance in lumbar degenerative disease. They present the study protocol RELApSE (NCT05448092 ID) and discuss the rationale through a comprehensive literature review., Results: From the 237 papers on this topic, a total of 176 articles were selected in this review. The analysis of these literature data shows sparse and variable evidence. There are no observations or guidelines about the value of lordosis restoration or PI-LL mismatch. Most of the works in the literature are retrospective, monocentric, based on small populations, and often address the topic evaluation partially., Conclusions: The RELApSE study is based on the possibility of comparing a heterogeneous population by pathology and different surgical technical options on some homogeneous clinical and anatomic-radiological measures aiming to understanding the value that global lumbar and segmental lordosis, distribution of lordosis, pelvic tilt, and PI-LL mismatch may have on clinical outcome in lumbar degenerative pathology and on the occurrence of adjacent segment disease., (© 2023 The Authors.)

This chapter describes the different types of aura including rare aura subtypes such as retinal aura. In addition, aura manifestations not classified in the International Classification of Headache Disorders and auras in headache disorders others than migraine are also described. The differential diagnosis of migraine aura comprises several neurological disorders which should be known to specialists. Migraine aura also has impact on the choice of migraine treatment; recommendations for the treatment of the migraine aura itself are also presented in this chapter., (Copyright © 2023 Elsevier B.V. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: The development of reproducible and sensitive outcome measures has been challenging in hereditary transthyretin (ATTRv) amyloidosis. Recently, quantification of intramuscular fat by magnetic resonance imaging (MRI) has proven as a sensitive marker in patients with other genetic neuropathies. The aim of this study was to investigate the role of muscle quantitative MRI (qMRI) as an outcome measure in ATTRv., Methods: Calf- and thigh-centered multi-echo T2-weighted spin-echo and gradient-echo sequences were obtained in patients with ATTRv amyloidosis with polyneuropathy (n = 24) and healthy controls (n = 12). Water T2 (wT2) and fat fraction (FF) were calculated. Neurological assessment was performed in all ATTRv subjects. Quantitative MRI parameters were correlated with clinical and neurophysiological measures of disease severity., Results: Quantitative imaging revealed significantly higher FF in lower limb muscles in patients with ATTRv amyloidosis compared to controls. In addition, wT2 was significantly higher in ATTRv patients. There was prominent involvement of the posterior compartment of the thighs. Noticeably, FF and wT2 did not exhibit a length-dependent pattern in ATTRv patients. MRI biomarkers correlated with previously validated clinical outcome measures, Polyneuropathy Disability scoring system, Neuropathy Impairment Score (NIS) and NIS-lower limb, and neurophysiological parameters of axonal damage regardless of age, sex, treatment and TTR mutation., Conclusions: Muscle qMRI revealed significant difference between ATTRv and healthy controls. MRI biomarkers showed high correlation with clinical and neurophysiological measures of disease severity making qMRI as a promising tool to be further investigated in longitudinal studies to assess its role at monitoring onset, progression, and therapy efficacy for future clinical trials on this treatable condition., (© 2022. The Author(s).)

Purpose: Dysphagia is a common symptom in patients with Parkinson's disease (PD), though it may go undiagnosed until severe complications arise. Dysphagia can be suspected on a clinical basis, but an instrumental assessment is mandatory to confirm its presence and evaluate pathophysiological aspects and severity of the swallowing impairment. Aim of this review is to inform the clinician and the radiologist on the importance and the main radiological findings of the Video-Fluoroscopic-Swallow-Study (VFSS) in patients with PD starting from the most recent literature data on the topic., Materials and Methods: Databases analysis identified 98 papers (January 2000/October 2022) of which 55 were excluded after reading title, abstract and full-text. After evaluation of the selected articles and their references 7 additional papers were added., Results: Fifty papers were reviewed to answer the following four main questions: Should VFSS be routinely used to screen dysphagia? Compared to other diagnostic tools, what is the role of VFSS in PD patients with suspected dysphagia? What are the main VFSS findings and technical expedients ? What is the role of VFSS in the choice of the best treatment strategy ?, Conclusions: VFSS represents a gold standard technique in the diagnostic evaluation of dysphagia in PD, having a fundamental role in the identification of patients with high risk of aspiration pneumonia and also being extremely helpful to guide to the choice of treatment strategies for dysphagia., (© 2022. Italian Society of Medical Radiology.)

Objective: The objective is to summarize the knowledge on the epidemiology, pathophysiology and management of secondary headache attributed to SARS-CoV-2 infection and vaccination; as well as to delineate their impact on primary headache disorders., Methods: This is a narrative review of the literature regarding primary and secondary headache disorders in the setting of COVID-19 pandemic. We conducted a literature search in 2022 on PubMed, with the keywords "COVID 19" or "vaccine" and "headache" to assess the appropriateness of all published articles for their inclusion in the review., Results: Headache is a common and sometimes difficult-to-treat symptom of both the acute and post-acute phase of SARS-CoV-2 infection. Different pathophysiological mechanisms may be involved, with the trigeminovascular system as a plausible target. Specific evidence-based effective therapeutic options are lacking at present. Headache attributed to SARS-CoV-2 vaccinations is also common, its pathophysiology being unclear. People with primary headache disorders experience headache in the acute phase of COVID-19 and after vaccination more commonly than the general population. Pandemic measures, forcing lifestyle changes, seemed to have had a positive impact on migraine, and changes in headache care (telemedicine) have been effectively introduced., Conclusions: The ongoing COVID-19 pandemic is a global challenge, having an impact on the development of secondary headaches, both in people with or without primary headaches. This has created opportunities to better understand and treat headache and to potentiate strategies to manage patients and ensure care.

Objective: Several studies have shown a strong association between alexithymia and psychological distress in both healthy and clinical populations. The aim of this study was to investigate the prevalence and association between alexithymia and psychological distress in individuals with fibromyalgia (FM) and chronic migraine (CM) compared with healthy controls (HC)., Methods: A cross-sectional study was conducted. Two hundred fifty women with FM (age: 51.2 ± 10.5) and 250 women with CM (age: 46.1 ± 11.5) were assessed with the Toronto Alexithymia Scale (TAS-20) and the Hospital Anxiety and Depression Scale (HADS) and compared with HCs (n = 280; age: 51.8 ± 9.0) by one-way analyses of variance. A moderation analysis was performed to examine the moderation effect of groups on the relationship between alexithymia and psychological distress., Results: Differences between groups showed significantly higher scores for TAS-20 [F(2,755) = 11.7, p < .001] and HADS [F(2,763) = 31.7, p < .001] in FM, compared with CM and HCs. The moderation analysis showed that both clinical groups and TAS-20 (β = 0.20, p < .001) were significant predictors, as well as the interaction terms. The slope of the correlation curve was more pronounced in the patient groups, indicating that the degree of alexithymia had a significantly higher influence on the HADS total score in the patient groups., Conclusion: The results suggest a common psychological dysregulation in FM and CM, with a slight but greater prevalence of alexithymia and psychological distress in FM. These data suggest that although there is a similar psychological substrate, it is expressed in a different expression of somatic symptoms., Competing Interests: Declaration of Competing Interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose of Review: Neurogenic dysphagia worsens quality of life and prognosis of patients with different neurological disorders. Management of neurogenic dysphagia can be challenging. This review provides a comprehensive overview of current evidence on screening, diagnosis, and treatment of neurogenic dysphagia in stroke and Parkinson's disease, suggesting clues for clinical practice., Recent Findings: The pros and cons of diagnostic techniques are discussed in the light of updated evidence. Findings from recent meta-analyses of different treatment approaches, including traditional dysphagia therapy, peripheral and central neurostimulation techniques, and treatment with botulinum toxin, are critically discussed, emphasizing inconsistencies and controversial issues., Summary: Screening tests and clinical swallow examination should be routinely performed in neurological patients at risk for dysphagia. In patients testing positive for dysphagia, first-line instrumental investigations, represented by fiberoptic endoscopic evaluation of swallowing or videofluoroscopic swallow study, should be performed to confirm the presence of dysphagia, to assess its severity, and to inform the treatment. Second-line and third-line instrumental methods can be used in selected patients to clarify specific pathophysiological aspects of oropharyngeal dysphagia. Treatment strategies should be personalized, and combination of traditional dysphagia therapy with innovative treatment approaches may increase the chance of restoring effective and safe swallowing., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: given the limited efficacy, tolerability, and accessibility of pharmacological treatments for chronic migraine (CM), new complementary strategies have gained increasing attention. Body ownership illusions have been proposed as a non-pharmacological strategy for pain relief. Here, we illustrate the protocol for evaluating the efficacy in decreasing pain perception of the enfacement illusion of a happy face observed through an immersive virtual reality (VR) system in CM., Method: the study is a double-blind randomized controlled trial with two arms, involving 100 female CM patients assigned to the experimental group or the control group. The experimental group will be exposed to the enfacement illusion, whereas the control group will be exposed to a pleasant immersive virtual environment. Both arms of the trial will consist in three VR sessions (20 min each). At the baseline and at the end of the intervention, the patients will fill in questionnaires based on behavioral measures related to their emotional and psychological state and their body satisfaction. Before and after each VR session, the level of pain, the body image perception, and the affective state will be assessed., Discussion: this study will provide knowledge regarding the relationship between internal body representation and pain perception, supporting the effectiveness of the enfacement illusion as a cognitive behavioral intervention in CM.

Preclinical data point to the contribution of transient receptor potential ankyrin 1 (TRPA1) channels to the complex mechanisms underlying migraine pain. TRPA1 channels are expressed in primary sensory neurons, as well as in glial cells, and they can be activated/sensitized by inflammatory mediators. The aim of this study was to investigate the relationship between TRPA1 channels and glial activation in the modulation of trigeminal hyperalgesia in preclinical models of migraine based on acute and chronic nitroglycerin challenges. Rats were treated with ADM&#95;12 (TRPA1 antagonist) and then underwent an orofacial formalin test to assess trigeminal hyperalgesia. mRNA levels of pro- and anti-inflammatory cytokines, calcitonin gene-related peptide (CGRP) and glia cell activation were evaluated in the Medulla oblongata and in the trigeminal ganglia. In the nitroglycerin-treated rats, ADM&#95;12 showed an antihyperalgesic effect in both acute and chronic models, and it counteracted the changes in CGRP and cytokine gene expression. In the acute nitroglycerin model, ADM&#95;12 reduced nitroglycerin-induced increase in microglial and astroglial activation in trigeminal nucleus caudalis area. In the chronic model, we detected a nitroglycerin-induced activation of satellite glial cells in the trigeminal ganglia that was inhibited by ADM&#95;12. These findings show that TRPA1 antagonism reverts experimentally induced hyperalgesia in acute and chronic models of migraine and prevents multiple changes in inflammatory pathways by modulating glial activation.

There is no gold-standard treatment for idiopathic toe walking (ITW). Some previous evidence suggested that botulinum neurotoxin-A injection might improve ITW. This is a single-center retrospective study on children with ITW treated with incobotulinumtoxinA injection in the gastrocnemius medialis/lateralis muscles. We screened the charts of 97 ITW children treated with incobotulinumtoxinA (January 2019-December 2021), and the data of 28 of them, who satisfied the inclusion/exclusion criteria, were analyzed. The maximal passive ankle dorsiflexion (knee extended) was assessed at three time points, i.e., immediately before incobotulinumtoxinA injection (T0), after incobotulinumtoxinA injection during the timeframe of its effect (T1), and at follow-up, when the effect was expected to disappear (T2). The maximal passive ankle dorsiflexion was improved by incobotulinumtoxinA injection, and the effect lasted up to 6 months in some children. No adverse effects were reported to incobotulinumtoxinA injections. The treatment with incobotulinumtoxinA might improve the maximal passive ankle dorsiflexion and is safe and well-tolerated in ITW with a longer-than-expected effect in comparison to cerebral palsy. These results may offer ground to future randomized controlled trials and studies assessing the effect of BoNT-A in combination with other non-invasive approaches and exercise programs in children with ITW.

Vestibular symptoms accompanying headache are quite common in migraine patients. Based on the association of vertigo with migraine, vestibular migraine was included in the appendix of the 3rd edition of the International Classification of Headache Disorders as a possible migraine subtype worthy of further investigation. In this post hoc, exploratory analysis, we investigated the occurrence of oculo-vestibular signs (OVSs) during experimentally induced migraine attacks in 24 episodic migraine patients and 19 healthy controls exposed to sublingual nitroglycerin (NTG - 0.9 mg). A comprehensive clinical examination was performed at baseline, at the onset of the migraine-like attack, and immediately before hospital discharge (180 minutes after NTG administration). Three of the 13 migraine patients who developed a spontaneous-like migraine attack during the hospital observation period (23.1%) also developed OVSs during the induction test. Noteworthy, none of the patients with a negative induction test developed OVSs and no OVSs were reported in healthy subjects at any time point. The exploratory nature of our study does not allow to draw definite conclusions on the possible implications of a vestibular dysfunction in migraine pathophysiology. Our results however suggest that NTG administration may lend itself to investigate vestibular dysfunction in migraine, at least in a subset of patients. The present findings represent a starting point for designing future ad hoc and well-powered studies., (© 2022. The Author(s).)

Background: Migraine-attributed burden, impact, disability and migraine-impacted quality of life are important concepts in clinical management, clinical and epidemiological research, and health policy, requiring clear and agreed definitions. We aimed to formulate concise and precise definitions of these concepts by expert consensus., Methods: We searched the terms migraine-attributed burden, impact, disability and migraine-impacted quality of life in Embase and Medline from 1974 and 1946 respectively. We followed a Delphi process to reach consensus on definitions., Results: We found widespread conflation of concepts and inconsistent terminology within publications. Following three Delphi rounds, we defined migraine-attributed burden as "the summation of all negative consequences of the disease or its diagnosis"; migraine-attributed impact as "the effect of the disease, or its diagnosis, on a specified aspect of life, health or wellbeing"; migraine-attributed disability as "physical, cognitive and mental incapacities imposed by the disease"; and migraine-impacted quality of life as "the subjective assessment by a person with the disease of their general wellbeing, position and prospects in life". We complemented each definition with a detailed description., Conclusion: These definitions and descriptions should foster consistency and encourage more appropriate use of currently available quantifying instruments and aid the future development of others.

Migraine is a complex neurovascular disorder characterized by recurrent attacks of pain and other associated symptoms. Emotional-affective aspects are important components of pain, but so far they have been little explored in animal models of migraine. In this study, we aimed to explore the correlation between trigeminal hyperalgesia and affective status or behavioral components in a migraine-specific animal model. Male Sprague-Dawley rats were treated with nitroglycerin (10 mg/kg, i.p.) or its vehicle. Four hours later, anxiety, motor/exploratory behavior and grooming (a nociception index) were evaluated with the open field test. Rats were then exposed to formalin in the orofacial region to evaluate trigeminal hyperalgesia. The data analysis shows an inverse correlation between trigeminal hyperalgesia and motor or exploratory behavior, and a positive association with anxiety-like behavior or self-grooming. These findings further expand on the translational value of the migraine-specific model based on nitroglycerin administration and prompt additional parameters that can be investigated to explore migraine disease in its complexity., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have recently been proposed as promising biomarkers in different immune-mediated disorders. We evaluated the plasma levels of MMP-9 and MMP-2 and their tissue inhibitors TIMP-1 and TIMP-2 in a patients' cohort with generalized myasthenia gravis (MG)., Methods: Plasma concentrations of MMP-9, MMP-2, TIMP-1 and TIMP-2 were evaluated in 14 patients with generalized MG and 13 age- and sex-matched healthy controls. The severity of disease was assessed by the modified Osserman classification., Results: Compared to the healthy subjects, MG patients had increased plasma concentrations of MMP-9, but reduced plasma levels of MMP-2 and TIMP-1. MG patients also showed a positive correlation between MMP-2 concentrations and disease severity. An increase in MMP-9 levels and MMP-9/TIMP-1 ratio and a decrease in MMP-2 levels and MMP-2/TIMP-2 ratio were detected in patients with generalized MG. Higher levels of MMP-2 correlated with greater disease severity., Discussion: Our preliminary findings suggest that MMPs and TIMPs could play a role in the pathogenesis of MG and might be associated with the risk of clinical deterioration.

Background: Smell and taste disturbances are among the most frequent neurological symptoms in patients with COVID-19. A concomitant impairment of the trigeminal nerve has been suggested in subjects with olfactory dysfunction, although it has not been confirmed with objective measurement techniques. In this study, we explored the trigeminal function and its correlations with clinical features in COVID-19 patients with impaired smell perception using electrophysiological testing., Methods: We enrolled 16 consecutive patients with mild COVID-19 and smell impairment and 14 healthy controls (HCs). Olfactory and gustatory symptoms were assessed with self-reported questionnaires. Electrophysiological evaluation of the masseter inhibitory reflex (MIR) and blink reflex (BR) was carried out to test the trigeminal function and its connections within the brainstem., Results: Masseter inhibitory reflex (MIR) analysis revealed higher latency of ipsilateral and contralateral early silent period in patients when compared with HCs. No significant differences between groups were detected as regards the duration of the early and late silent period. However, several patients showed a prolonged duration of the early silent period. BR evaluation disclosed only an increased amplitude of early components in patients., Conclusions: Patients with COVID-19 and smell impairment show a subclinical trigeminal nerve impairment. Trigeminal alterations mainly involve the oligosynaptic pathway, as a result of either direct viral damage or secondary neuroinflammation of the peripheral trigeminal fibers, whereas the polysynaptic ponto-medullary circuits seem to be spared. The prolonged duration of the early silent period and the increased amplitude of early BR response might reflect a compensatory upregulation of the trigeminal function as a consequence of the olfactory dysfunction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cosentino, Maiorano, Todisco, Prunetti, Antoniazzi, Tammam, Quartesan, Lettieri, De Icco, Corsico, Benazzo, Pisani, Tassorelli and Alfonsi.)

Clinic-based headache registries collect data for a wide variety of purposes including delineating disease characteristics, longitudinal natural disease courses, headache management approaches, quality of care, treatment safety and effectiveness, factors that predict treatment response, health care resource utilization, clinician adherence to guidelines, and cost-effectiveness. Registry data are valuable for numerous stakeholders, including individuals with headache disorders and their caregivers, healthcare providers, scientists, healthcare systems, regulatory authorities, pharmaceutical companies, employers, and policymakers. This International Headache Society document may serve as guidance for developing clinic-based headache registries. Use of registry data requires a formal research protocol that includes: 1) research aims; 2) methods for data collection, harmonization, analysis, privacy, and protection; 3) methods for human subject protection; and 4) publication and dissemination plans. Depending upon their objectives, headache registries should include validated headache-specific questionnaires, patient reported outcome measures, data elements that are used consistently across studies (i.e., "common data elements"), and medical record data. Amongst other data types, registries may be linked to healthcare and pharmacy claims data, biospecimens, and neuroimaging data. Headache diagnoses should be made according to the International Classification of Headache Disorders diagnostic criteria. The data from well-designed headache registries can provide wide-ranging and novel insights into the characteristics, burden, and treatment of headache disorders and ultimately lead to improvements in the management of patients with headache.

Calcitonin-gene-related peptide (CGRP) plays a key role in migraine pathophysiology and more specifically in the mechanisms underlying peripheral and central sensitization. Here, we explored the interaction of CGRP with other pain mediators relevant for neuronal sensitization in an animal model of chronic migraine. Male Sprague-Dawley rats were exposed to nitroglycerin (NTG, 5 mg/kg, i.p.) or vehicle co-administered with the CGRP receptor antagonist olcegepant (2 mg/kg i.p.), or its vehicle, every other day over a 9-day period. Twenty-four hours after the last injection of NTG (or vehicle), behavioral test and ex vivo analysis were performed. Olcegepant attenuated NTG-induced trigeminal hyperalgesia in the second phase of the orofacial formalin test. Interestingly, it also reduced gene expression and protein levels of CGRP, pro-inflammatory cytokines, inflammatory-associated miRNAs (miR-155-5p, miR-382-5p, and miR-34a-5p), and transient receptor potential ankyrin channels in the medulla-pons area, cervical spinal cord, and trigeminal ganglia. Similarly, olcegepant reduced the NTG-induced increase in CGRP and inflammatory cytokines in serum. The findings show that the activation of the CGRP pathway in a migraine animal model was associated to the persistent activation of inflammatory pathways, which was paralleled by a condition of hyperalgesia. These molecular events are relevant for informing us about the mechanisms underlying chronic migraine.

Background: In Italy, monoclonal antibodies targeting the CGRP pathway are subsidized for the preventive treatment of high frequency and chronic migraine (CM) in patients with a MIgraine Disability ASsessment (MIDAS) score ≥ 11. Eligibility to treatment continuation requires a ≥ 50% MIDAS score reduction at three months (T3). In this study, we evaluate whether a ≥ 50% MIDAS score reduction at T3 is a reliable predictor of response to one-year erenumab treatment., Methods: In this prospective, open-label, real-world study, 77 CM patients were treated with erenumab 70-140 mg s.c. every 28 days for one year (T13). We collected the following variables: monthly migraine days (MMDs), monthly headache days (MHDs), days of acute medication intake, MIDAS, HIT-6, anxiety, depression, quality of life and allodynia. Response to erenumab was evaluated as: i) average reduction in MMDs during the 1-year treatment period; and ii) percentage of patients with ≥ 50% reduction in MMDs during the last 4 weeks after the 13 th injection (Responders T13 )., Results: Erenumab induced a sustained reduction in MMDs, MHDs and intake of acute medications across the 12-month treatment period, with 64.9% of patients qualifying as Responders T13 . At T3, 55.8% of patients reported a ≥ 50% reduction in MIDAS score (MIDAS Res ) and 55.4% of patients reported a ≥ 50% reduction in MMDs (MMD Res ). MIDAS Res and MMD Res patients showed a more pronounced reduction in MMDs during the 1-year treatment as compared to NON-MIDAS Res (MIDAS Res : T0: 23.5 ± 4.9 vs. T13: 7.7 ± 6.2; NON- MIDAS Res : T0: 21.6 ± 5.4 vs. T13: 11.3 ± 8.8, p = 0.045) and NON-MMD Res (MMD Res : T0: 23.0 ± 4.5 vs. T13: 6.6 ± 4.8; NON-MMD Res : T0: 22.3 ± 6.0 vs. T13: 12.7 ± 9.2, p < 0.001) groups. The percentage of Responders T13 did not differ between MIDAS Res (74.4%) and NON-MIDAS Res (52.9%) patients (p = 0.058), while the percentage of Responders T13 was higher in the MMD Res group (83.3%) when compared to NON-MMD Res (42.9%) (p = 0.001). MMD Res predicted the long-term outcome according to a multivariate analysis (Exp(B) = 7.128; p = 0.001), while MIDAS Res did not. Treatment discontinuation based on MIDAS Res would have early excluded 36.0% of Responders T13 . Discontinuation based on "either MIDAS Res or MMD Res " would have excluded a lower percentage (16%) of Responders T13 ., Conclusion: MIDAS Res only partly reflects the 12-month outcome of erenumab treatment in CM, as it excludes more than one third of responders. A criterion based on the alternative consideration of ≥ 50% reduction in MIDAS score or MMDs in the first three months of treatment represents a more precise and inclusive option., Trial Registration: The trial was retrospectively registered at www., Clinicaltrials: gov (NCT05442008). CGRP: Calcitonin Gene Related Peptide., Midas: MIgraine Disability Assessment. MMDs: monthly migraine days. MIDAS Res : Patients with a MIDAS score reduction of at least 50% at T3. MMD Res : Patients with a MMDs reduction of at least 50% at T3. Responder T13 : Patients with a MMDs reduction from baseline of at least 50% in the last 4 weeks of observation period (after 13 erenumab administrations). T0: First erenumab administration. T3, T6, T9, T12: Follow-up visits at three, six, nine, and twelve months after first erenumab administration. T13: Last visit of the protocol., (© 2022. The Author(s).)