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Background: Migraine with aura (MwA) is a debilitating disorder characterized by paroxysmal attacks of pain preceded or accompanied by reversible neurological symptoms. While the pathophysiology remains unclear, trigeminovascular system activation and cortical spreading depression have been implicated. This study aims to comprehensively investigate and characterize the diverse clinical features and manifestations of aura, as well as the types of acute medications self-administered for aura management., Methods: A multicenter, cross-sectional study was conducted using data from the Italian Headache Registry (RICe). Aura characteristics, frequency, duration and associated migraine premonitory symptoms were collected. Acute medication use and timing (headache or aura phase) were assessed., Results: The study included 272 patients with a diagnosis of MwA. Most patients (99.3%) experienced typical aura symptoms, with visual aura (96.3%) being the most prevalent, followed by sensory (33.0%) and speech and/or language aura (25.6%). Brainstem aura (8.5%) and motor aura (1.8%) were less common. Notably, 13.0% of patients reported aura relapses within 24 hours. Triptans (39.7%), non-steroidal anti-inflammatory drugs (47.8%) and nutraceuticals (59.9%) were commonly used for acute aura management., Conclusions: This study reports several different aura manifestations, highlighting atypical features, aura relapse rates and treatment approaches for aura. These findings could contribute to a deeper understanding of aura and its management in clinical settings., 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: PG received personal fees from Allergan, Eli Lilly, Novartis, Amgen and TEVA; grants from Amgen, TEVA, Eli-Lilly, Allergan and Chiesi; is on the Scientific Advisory Board for Endosome Therapeutics; and is a founding scientist of FloNext srl, Spinoff of the University of Florence. FDC received personal fees from TEVA, Eli Lilly and Novartis. LFI received personal fees from Eli-Lilly and TEVA, and a travel grant from Lundbeck. SS reports personal fees as a speaker or advisor from Abbott, Allergan-AbbVie, AstraZeneca, Eli Lilly, Lundbeck, Novartis, NovoNordisk, Pfizer and Teva, and research grants from Novartis. RO reports personal fees from Novartis, Eli Lilly and Teva, and non-financial support from Novartis, Allergan, Eli Lilly and Teva. SG received personal fees from Allergan/AbbVie, Eli Lilly, Novartis, Teva and Lundbeck. Grazia Sances received personal fees as a speaker or was on the Advisory Board for Eli-Lilly, Novartis, TEVA, Lundbeck and Pfizer. RDI received speaker honoraria and advisory board participation: Eli-Lilly, TEVA, Lundbeck, Pfizer, AbbVie; MPP received speaker honoraria and advisory board participation from Abbvie, Idorsia, Eli-Lilly, Novartis, Pfizer, TEVA. The other authors have no conflicting interests.

Background: The anti-calcitonin gene-related peptide (CGRP), or its receptor (CGRP/R) monoclonal antibodies (mAbs), offer targeted, effective, and tolerated drugs for migraine. However, about 25% of patients fail to achieve a clinically meaningful response, usually leading to discontinuation. These patients often have a lengthy migraine history and multiple prior preventive treatment failures, resulting in limited therapeutic options. Herein, we describe the cause for and outcome of withdrawal of anti-CGRP/R mAb and evaluate the treatment course until discontinuation., Methods: We conducted a prospective analysis on migraine patients attending the Florence Headache Center in Italy, who discontinued treatment with anti-CGRP/R mAbs. The primary objectives were to describe the reasons for anti-CGRP mAbs discontinuation and the treatment course. Secondary objectives were the evaluation of the absolute change from baseline in monthly headache days, response rates, persistence in medication overuse, absolute change from baseline of the overall number and days of analgesics use per month, change of MIDAS and HIT-6 at three, six, and 12 months, and the last month of treatment., Results: Among 472 patients, 136 (28.8%) discontinued mAb treatment after an average of 9.0 ± 6.1 (mean ± SD) months. The majority (96/136, 70.6%) discontinued due to ineffectiveness, followed by lost to follow-up during treatment (18/136, 13.1%) and adverse events (10/136, 7.3%). In total, 77.9% of the 136 patients ceased treatment within the first year. Following discontinuation, 48.5% initiated new pharmacological treatment, 39.7% were lost to follow-up, and 11.8% opted not to start another treatment. The majority of patients that started a new pharmacology treatment switched to another anti-CGRP/R (46/68, 67.6%). The second most-used treatment was onabotulinumtoxinA (7/68, 10.2%; all patients in this subgroup were naïve to this treatment), followed by an anticonvulsive medication (7/68, 10.2%). The response status (≥50% reduction in monthly headache days) was achieved by 30.5%, 34.6%, and 40.0% of patients at month 3, 6, and 12 of treatment, respectively. Considering only the comprehensive last month of treatment before withdrawn the percentage of responders was 16.9%., Conclusion: Although anti-CGRP/R mAbs have provided a substantial amelioration of migraine management, a relevant proportion of patients remains unresponsive and requires additional therapeutic support. Further research is required to identify non-responder features and address unmet needs in migraine treatment., 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: P.G.: received personal fees from Allergan, Eli Lilly, Novartis, Amgen, TEVA; Grants from Amgen, TEVA, Eli-Lilly, Allergan, Chiesi; Scientific Advisory Board, Endosome Therapeutics; Founding scientist of FloNext srl, Spinoff of the University of Florence.F.D.C. received personal fees from TEVA, Eli Lilly, Novartis, Abbvie.B.R. reports research grants from Novartis, and personal fees from Abbvie/Allergan, Hormosan, Lilly, Novartis, and Teva.R.D.I. received honoraria for scientific presentations from Eli-Lilly and Teva.L.F.I. received personal fees from TEVA, Eli Lilly, Pfizer, Abbvie, Lundbeck.Other authors have no conflicting interests.

Background: High-frequency episodic migraine (HFEM) has gained attention in the field of headache research and clinical practice. In this narrative review, we analyzed the available literature to assess the evidence that could help decide whether HFEM may represent a distinct clinical and/or biological entity within the migraine spectrum., Methods: The output of the literature search included 61 papers that were allocated to one of the following topics: (i) socio-demographic features and burden; (ii) clinical and therapeutic aspects; (iii) pathophysiology; and (iv) classification., Results: Multiple features differentiate subjects with HFEM from low-frequency episodic migraine and from chronic migraine: education, employment rates, quality of life, disability and psychiatric comorbidities load. Some evidence also suggests that HFEM bears a specific profile of activation of cortical and spinal pain-related pathways, possibly related to maladaptive plasticity., Conclusions: Subjects with HFEM bear a distinctive clinical and socio-demographic profile within the episodic migraine group, with a higher disease burden and an increased risk of transitioning to chronic migraine . Recognizing HFEM as a distinct entity is an opportunity for the better understanding of migraine and the spectrum of frequency with which it can manifest, as well as for stimulating further research and more adequate public health approaches., 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 (past 4 years). FC: None. RDI received personal fees for participating in speaking at scientific events from Eli-Lilly, TEVA and Lundbeck. He has participated in an advisory board for Pfizer and AbbVie. MC: None. FB: None. GV received personal fees for participating in speaking at scientific events from Lundbeck. DM reports support from Abbvie for participating in advisory boards; consulting fees from LifeSciences Consultants, fees from Medscape for organizing educational programs; and personal fees from Lundbeck for lecturing at symposia. PP-R reports support for the present study from AbbVie and personal fees for consulting from AbbVie, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer and Teva. She has received personal fees for speaking from AbbVie, Dr Reddy's, Eli Lilly, Lundbeck, Medscape, Novartis and Teva, and has had grants paid to her research group from AbbVie, AGAUR, EraNet Neuron, FEDER RIS3CAT, Instituto Investigacion Carlos III, International Headache Society, Novartis and Teva. She is a member of the Scientific Advisory Board for Lilly Foundation Spain.PJG reports, over the last 36 months, grants from Celgene and Kallyope; personal fees from Aeon Biopharma, Abbvie, Amgen, eNeura, CoolTech LLC, Dr Reddys’, Eli-Lilly and Company, Epalex, Linpharma, Lundbeck, Man&Science, Novartis, Pfizer, Sanofi, Satsuma, Shiratronics and Teva Pharmaceuticals; personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners and Vector Metric; fees for educational materials from CME Outfitters; as well as publishing royalties or fees from Massachusetts Medical Society, Oxford University Press, UptoDate and Wolters Kluwer. CT reports support from Abbvie and Novartis for investigator-initiated trials; consulting fees from Abbvie, Eli Lilly, Dompé, Ipsen, Lundbeck, Pfizer, Teva and Medscape for participating in advisory boards; support from Abbvie, Eli Lilly, Dompé, Ipsen, Lundbeck, Pfizer and Teva for attending meetings; and personal fees from Abbvie, Eli Lilly, Lundbeck, Pfizer and Teva for lecturing at symposia. She is principal investigator of clinical trials sponsored by Abbvie, Biohaven, Eli Lilly, Ipsen, Lundbeck, Pfizer and Teva. She has received research grants from the European Commission, the Italian Ministry of Health and the Migraine Research Foundation.

Background : Stroke-induced immunosuppression (SII) represents a negative rehabilitative prognostic factor associated with poor motor performance at discharge from a neurorehabilitation unit (NRB). This study aims to evaluate the association between SII and gait impairment at NRB admission. Methods : Forty-six stroke patients (65.4 ± 15.8 years, 28 males) and 42 healthy subjects (HS), matched for age, sex, and gait speed, underwent gait analysis using an inertial measurement unit at the lumbar level. Stroke patients were divided into two groups: (i) the SII group was defined using a neutrophil-to-lymphocyte ratio ≥ 5, and (ii) the immunocompetent (IC) group. Harmonic ratio (HR) and short-term largest Lyapunov's exponent (sLLE) were calculated as measures of gait symmetry and stability, respectively. Results : Out of 46 patients, 14 (30.4%) had SII. HR was higher in HS when compared to SII and IC groups ( p < 0.01). HR values were lower in SII when compared to IC subjects ( p < 0.01). sLLE was lower in HS when compared to SII and IC groups in the vertical and medio-lateral planes ( p ≤ 0.01 for all comparisons). sLLE in the medio-lateral plane was higher in SII when compared to IC subjects ( p = 0.04). Conclusions : SII individuals are characterized by a pronounced asymmetric gait and a more impaired dynamic gait stability. Our findings underline the importance of devising tailored rehabilitation programs in patients with SII. Further studies are needed to assess the long-term outcomes and the role of other clinical features on gait pattern.

Background: miR-155 is involved in the generation and maintenance of inflammation and pain, endothelial function and immune system homeostasis, all functions that are relevant for migraine. The present study aims to assess the levels of miR-155 in migraine subtypes (episodic and chronic) in comparison to age- and sex-matched healthy controls., Methods: This is a cross-sectional, controlled, study involving three study groups: I) episodic migraine (n = 52, EM), II) chronic migraine with medication overuse (n = 44, CM-MO), and III) healthy controls (n = 32, HCs). We assessed the interictal gene expression levels of miR-155, IL-1β, TNF-α, and IL-10 in peripheral blood monocytes using rtPCR. The monocytic differentiation toward the M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes was assessed in circulating monocytes with flow cytometry analysis and cell sorting., Results: miR-155 gene expression was higher in CM-MO group (2.68 ± 2.47 Relative Quantification - RQ) when compared to EM group (1.46 ± 0.85 RQ, p = 0.006) and HCs (0.44 ± 0.18 RQ, p = 0.001). In addition, miR-155 gene expression was higher in EM group when compared to HCs (p = 0.001). A multivariate analysis confirmed the difference between EM and CM-MO groups after correction for age, sex, smoking habit, preventive treatment, aura, presence of psychiatric or other pain conditions. We found higher gene expression of IL-1β, TNF-α, and lower gene expression of IL-10 in migraine participants when compared to HCs (p = 0.001 for all comparisons). TNF-α and IL-10 genes alterations were more prominent in CM-MO when compared to EM participants (p = 0.001). miR-155 positively correlated with IL-1β (p = 0.001) and TNF-α (p = 0.001) expression levels. Finally, in people with CM-MO, we described an up-regulated percentage of events in both M1 and M2 monocytic profiles., Conclusions: Our study shows for the first time a specific profile of activation of miR-155 gene expression levels in monocytes of selected migraine subpopulations, more pronounced in subjects with CM-MO. Interestingly, mir-155 expression correlated with markers of activation of the inflammatory and immune systems. The CM-MO subpopulation showed a peculiar increase of both pro-inflammatory and anti-inflammatory monocytes which worths further investigation., Trial Registration: www., Clinicaltrials: gov . (NCT05891808)., (© 2024. The Author(s).)

Objective: To confirm a previously reported association of TRPV1 rs8065080 with the risk of transformation from episodic (EM) to chronic migraine (CM) and to extend knowledge about the role of other TRPV1 single nucleotide polymorphisms (SNPs), we first investigated the impact of three TRPV1 SNPs (rs8065080, rs222747 and rs222749) on the risk of migraine chronification in a case-control study. A systematic review and meta-analysis were then conducted to summarize the accumulated findings., Methods: Genotyping of the selected TRPV1 SNPs was performed using TaqMan real-time PCR in 167 EM and 182 CM participants. Crude and adjusted odds ratios with associated 95% confidence intervals were calculated in the log-additive, dominant, and recessive genetic models. A comprehensive literature search was performed in PubMed, Web of Knowledge, Cochrane Library, and OpenGrey until February 2024., Results: In our case-control study, no association was found between TRPV1 SNPs and the risk of migraine chronification, both in the unadjusted logistic regression models and after adjustment for confounding clinical variables. The results of the meta-analysis with a total of 241 participants with EM and 223 with CM confirmed no association between TRPV1 SNPs and the risk of migraine chronification in any of the genetic models tested., Conclusion: The results of the present case-control study and meta-analysis exclude a major role of TRPV1 rs8065080, rs222747, and rs222749 as risk factors for migraine chronification. However, further research is needed to investigate the gene-gene and gene-environment interactions of TRPV1 SNPs on the risk of transformation from episodic to chronic migraine., (© 2024. The Author(s).)

Background: Currently, the impact of drug therapies on neurodegenerative conditions is limited. Therefore, there is a strong clinical interest in non-pharmacological interventions aimed at preserving functionality, delaying disease progression, reducing disability, and improving quality of life for both patients and their caregivers. This longitudinal multicenter Randomized Controlled Trial (RCT) applies three innovative cognitive telerehabilitation (TR) methods to evaluate their impact on brain functional connectivity reconfigurations and on the overall level of cognitive and everyday functions., Methods: We will include 110 participants with mild cognitive impairment (MCI). Fifty-five participants will be randomly assigned to the intervention group who will receive cognitive TR via three approaches, namely: (a) Network-based Cognitive Training (NBCT), (b) Home-based Cognitive Rehabilitation (HomeCoRe), or (c) Semantic Memory Rehabilitation Training (SMRT). The control group ( n  = 55) will receive an unstructured home-based cognitive stimulation. The rehabilitative program will last either 4 (NBTC) or 6 weeks (HomeCoRe and SMRT), and the control condition will be adapted to each TR intervention. The effects of TR will be tested in terms of Δ connectivity change, obtained from high-density electroencephalogram (HD-EEG) or functional magnetic resonance imaging at rest (rs-fMRI), acquired before (T0) and after (T1) the intervention. All participants will undergo a comprehensive neuropsychological assessment at four time-points: baseline (T0), within 2 weeks (T1), and after 6 (T2) and 12 months (T3) from the end of TR., Discussion: The results of this RCT will identify a potential association between improvement in performance induced by individual cognitive TR approaches and modulation of resting-state brain connectivity. The knowledge gained with this study might foster the development of novel TR approaches underpinned by established neural mechanisms to be validated and implemented in clinical practice. Clinical trial registration: [https://classic.clinicaltrials.gov/ct2/show/NCT06278818], identifier [NCT06278818]., Competing Interests: The authors declare that the research will be 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 © 2024 Caminiti, Bernini, Bottiroli, Mitolo, Manca, Grillo, Avenali, De Icco, Capellari, Carlesimo, Venneri and Tassorelli.)

The interpretability of gait analysis studies in people with rare diseases, such as those with primary hereditary cerebellar ataxia (pwCA), is frequently limited by the small sample sizes and unbalanced datasets. The purpose of this study was to assess the effectiveness of data balancing and generative artificial intelligence (AI) algorithms in generating synthetic data reflecting the actual gait abnormalities of pwCA. Gait data of 30 pwCA (age: 51.6 ± 12.2 years; 13 females, 17 males) and 100 healthy subjects (age: 57.1 ± 10.4; 60 females, 40 males) were collected at the lumbar level with an inertial measurement unit. Subsampling, oversampling, synthetic minority oversampling, generative adversarial networks, and conditional tabular generative adversarial networks (ctGAN) were applied to generate datasets to be input to a random forest classifier. Consistency and explainability metrics were also calculated to assess the coherence of the generated dataset with known gait abnormalities of pwCA. ctGAN significantly improved the classification performance compared with the original dataset and traditional data augmentation methods. ctGAN are effective methods for balancing tabular datasets from populations with rare diseases, owing to their ability to improve diagnostic models with consistent explainability.

Stroke affects the interconnection between the nervous and immune systems, leading to a down-regulation of immunity called stroke-induced immunosuppression (SII). The primary aim of this study is to investigate SII role as a predictor of functional, neurological, and motor outcomes in the neurorehabilitation setting (NRB). We conducted a prospective observational study enrolling post-acute stroke patients hospitalized for neurorehabilitation. At NRB admission (T 0 ) and discharge (T 1 ), we assessed presence of SII (defined by a neutrophil-to-lymphocyte ratio ≥ 5) and we evaluated functional independence (Functional Independence Measure-FIM, Barthel Index-BI), motor performances (Tinetti Score, Hauser Ambulation Index) and neurological impairment (NIHSS). We enrolled 96 patients (45.8% females, 70.6 ± 13.9 years, 88.5% ischemic stroke). At T 0 , 15.6% of patients (15/96) had SII. When compared to immunocompetent patients (IC), the SII group was characterized by worse baseline functional independence, motor performances and neurological disability. The same was confirmed at T 1 (FIM p = 0.012, BI p = 0.007, Tinetti p = 0.034, NIHSS p = 0.001). Neurological disability demonstrated a less pronounced improvement in SII (ΔNIHSS: SII: - 2.1 ± 2.3 vs. IC: - 3.1 ± 2.5, p = 0.035). SII group presented a higher percentage of infectious complications during the neurorehabilitation period (SII 80% vs. IC 25.9%; p = 0.001). SII may represent a negative prognostic factor in the neurorehabilitation setting. SII patients were characterized by poorer functional, motor, neurological performances and higher risk of infectious complications. ClinicaTrial registration: NCT05889169., (© 2024. The Author(s).)

Theory of Mind (ToM) is the ability to infer one's own and others' mental states. Growing research indicates that ToM is impaired in Chronic Migraine with Medication Overuse (CM + MO). However, the research in this field has been conducted using static scenario-based tasks, often failing to test mentalization in everyday situations and measuring only performance accuracy. We filled this gap by administering the Movie for the Assessment of Social Cognition (MASC) to subjects with CM + MO compared to episodic migraine (EM). This test allows us to assess both affective and cognitive ToM and which, in addition to being accurate, also analyzes the type of error in attribution of mental states, distinguishing between hypo-mentalization and hyper-mentalization. Thirty patients suffering from CM + MO and 42 from EM were enrolled. Results showed that CM + MO patients were less accurate in mental state attribution than EM. In addition, compared to EM, CM + MO individuals were more impaired in the affective ToM dimensions and committed more errors of hypo-mentalization. In conclusion, the application of MASC in patients with CM + MO allowed for the detection of an alteration in their ability to correctly draw conclusions about other people's mental states. This latter contributes critically to appropriate social reactions and also, possibly, to satisfactory social interactions., (© 2024. The Author(s).)

Resistant migraine characterizes those patients who have failed at least three classes of migraine prophylaxis. These difficult-to-treat patients are likely to be characterized by a high prevalence of psychological disturbances. A dysfunction of the endocannabinoid system (ECS), including alteration in the levels of endocannabinoid congeners, may underlie several psychiatric disorders and the pathogenesis of migraines. Here we explored whether the peripheral gene expression of major components of the ECS and the plasma levels of endocannabinoids and related lipids are associated with psychological disorders in resistant migraine. Fifty-one patients (age = 46.0 ± 11.7) with resistant migraine received a comprehensive psychological evaluation according to the DSM-5 criteria. Among the patients, 61% had personality disorders (PD) and 61% had mood disorders (MD). Several associations were found between these psychological disorders and peripheral ECS alterations. Lower plasma levels of palmitoiletanolamide (PEA) were found in the PD group compared with the non-PD group. The MD group was characterized by lower mRNA levels of diacylglycerol lipase α ( DAGL α) and CB2 (cannabinoid-2) receptor. The results suggest the existence of peripheral dysfunction in some components of the ECS and an alteration in plasma levels of PEA in patients with resistant migraine and mood or personality disorders.

Migraine is a ubiquitous neurologic disorder that afflicts more than 1 billion people worldwide. Recommended therapeutic strategies include the use of acute and, if needed, preventive medications. During the past 2 decades, tremendous progress has been made in better understanding the molecular mechanisms underlying migraine pathogenesis, which in turn has resulted in the advent of novel medications targeting signaling molecule calcitonin gene-related peptide or its receptor. Here, we provide an update on the rational use of pharmacotherapies for migraine to facilitate more informed clinical decision-making. We then discuss the scientific discoveries that led to the advent of new medications targeting calcitonin gene-related peptide signaling. Last, we conclude with recent advances that are being made to identify novel drug targets for migraine., (Copyright © 2023 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Multiple sclerosis is an inflammatory and neurodegenerative disorder of the central nervous system that can lead to severe motor disability. The aim of this study was to verify the health care effects of an integrated telerehabilitation approach involving dual-domains (motor and cognitive) in people with multiple sclerosis using a virtual reality rehabilitation system compared to a home-based conventional rehabilitative intervention usual care for patient-relevant outcomes (motor, cognitive and participation)., Methods: This multicentre interventional, randomized controlled trial included 70 participants with multiple sclerosis, 35 in the telerehabilitation group (30 sessions of home-based virtual reality rehabilitation system training, five sessions for week each lasting 45 min) and 35 in the usual care group (30 sessions of conventional treatment, five sessions for week). Participants completed the assessment of motor, cognitive and participation outcomes at baseline and after 6 weeks of treatment., Results: In total, 63.3% of the telerehabilitation group exhibited improvement in the physical domain of the quality of life ( p  = 0.045). The telerehabilitation group showed greater improvement than the usual care group in Mini-BESTest domains of balance ( p  = 0.014), postural control ( p  = 0.024), and dynamic walking ( p  = 0.020) at post-treatment. Higher adherence was registered for telerehabilitation compared with usual care (86.67% vs . 80.0%)., Discussion: This study provides evidence that people with multiple sclerosis can benefit from telerehabilitation treatment in the physical domain of the quality of life and motor symptoms. Moreover, considering the persistent COVID-19 emergency, telerehabilitation can represent an effective telemedicine solution for safely delivering effective rehabilitation care to people with multiple sclerosis., Trial Registration Number and Trial Register: This trial was registered at ClinicalTrials.gov (NCT03444454)., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Background: Headache disorders are a global public health concern affecting diverse populations. This review examines headache service organizations in low-, middle-, and high-income countries. It addresses global challenges in pharmacological headache treatment, with a focus on safety, tolerability, reproductive and child health, and outlines disparities in accessing innovative treatments worldwide., Main Body: Organized headache services are essential due to the wide prevalence and varying severity of headache disorders. The tiered headache service model is globally recognized, although its implementation varies based on financial and workforce considerations. Headache burden affects well-being, causing disability, economic challenges, and work limitations, irrespective of location or income. All nations still require improved diagnosis and treatment, and the majority of countries face obstacles including limited access, awareness, economic barriers, and inadequate health policies. Provided adequate internet availability, telemedicine could help improve health equity by expanding access to headache care, since it can offer patients access to services without lengthy waiting times or extensive travel and can provide healthcare unavailable in underserved areas due to staff shortages. Numerous health disparities restrict global access to many headache medications, especially impacting individuals historically excluded from randomized controlled trials, such as those with cardiovascular and cerebrovascular conditions, as well as pregnant women. Furthermore, despite advancements in researching migraine treatments for young patients, the options for treatment remain limited. Access to headache treatment relies on factors like medication availability, approval, financial coverage, and healthcare provider expertise. Inadequate public awareness leads to neglect by policymakers and undertreatment by patients and healthcare providers. Global access discrepancies are exacerbated by the introduction of novel disease-specific medications, particularly impacting Asian, African, and Latin American nations excluded from clinical trials. While North America and Europe experience broad availability of migraine treatments, the majority of countries worldwide lack access to these therapies., Conclusions: Healthcare disparities, treatment access, and medication availability are concerning issues in headache medicine. Variations in national healthcare systems impact headache management, and costly innovative drugs are widening these gaps. Healthcare practitioners and experts should acknowledge these challenges and work towards minimizing access barriers for equitable global headache care in the future., (© 2023. The Author(s).)

Stroke, a leading cause of long-term disability worldwide, manifests as motor, speech language, and cognitive impairments, necessitating customized rehabilitation strategies. In this context, telerehabilitation (TR) strategies have emerged as promising solutions. In a multi-center longitudinal pilot study, we explored the effects of a multi-domain TR program, comprising physiotherapy, speech therapy, and neuropsychological treatments. In total, 84 stroke survivors (74 analyzed) received 20 tailored sessions per domain, addressing individual impairments and customized to their specific needs. Positive correlations were found between initial motor function, cognitive status, independence in activities of daily living (ADLs), and motor function improvement after TR. A lower initial health-related quality of life (HRQoL) perception hindered progress, but improved ADL independence and overall health status, and reduced depression correlated with a better QoL. Furthermore, post-treatment improvements were observed in the entire sample in terms of fine motor skills, upper-limb functionality, balance, independence, and cognitive impairment. This multi-modal approach shows promise in enhancing stroke rehabilitation and highlights the potential of TR in addressing the complex needs of stroke survivors through a comprehensive support and interdisciplinary collaboration, personalized for each individual's needs.

Background: The implementation of regular prolonged, and effective rehabilitation in people with Parkinson's disease is essential for ensuring a good quality of life. However, the continuity of rehabilitation care may find barriers related to economic, geographic, and social issues. In these scenarios, telerehabilitation could be a possible solution to guarantee the continuity of care., Aim: To investigate the efficacy of non-immersive virtual reality-based telerehabilitation on postural stability in people with Parkinson's disease, compared to at-home self-administered structured conventional motor activities., Design: Multicenter randomized controlled trial., Setting: Five rehabilitation hospitals of the Italian Neuroscience and Rehabilitation Network., Population: Individuals diagnosed with Parkinson's disease., Methods: Ninety-seven participants were randomized into two groups: 49 in the telerehabilitation group (non-immersive virtual reality-based telerehabilitation) and 48 in the control group (at-home self-administered structured conventional motor activities). Both treatments lasted 30 sessions (3-5 days/week for, 6-10 weeks). Static and dynamic balance, gait, and functional motor outcomes were registered before and after the treatments., Results: All participants improved the outcomes at the end of the treatments. The primary outcome (mini-Balance Evaluation Systems Test) registered a greater significant improvement in the telerehabilitation group than in the control group. The gait and endurance significantly improved in the telerehabilitation group only, with significant within-group and between-group differences., Conclusions: Our results showed that non-immersive virtual reality-based telerehabilitation is feasible, improves static and dynamic balance, and is a reasonably valuable alternative for reducing postural instability in people with Parkinson's disease., Clinical Rehabilitation Impact: Non-immersive virtual reality-based telerehabilitation is an effective and well-tolerated modality of rehabilitation which may help to improve access and scale up rehabilitation services as suggested by the World Health Organization's Rehabilitation 2030 agenda.

Background: Real-world studies on fremanezumab, an anti-calcitonin gene-related peptide monoclonal antibody for migraine prevention, are few and with limited follow-up., Objective: We aimed to evaluate the long-term (up to 52 weeks) effectiveness and tolerability of fremanezumab in high-frequency episodic migraine and chronic migraine., Methods: This s an independent, prospective, multicenter cohort study enrolling outpatients in 17 Italian Headache Centers with high-frequency episodic migraine or chronic migraine and multiple preventive treatment failures. Patients were treated with fremanezumab 225 mg monthly. The primary outcomes included changes from baseline (1 month before treatment) in monthly headache days, response rates (reduction in monthly headache days from baseline), and persistence in medication overuse at months 3, 6, and 12 (all outcome timeframes refer to the stated month). Secondary outcomes included changes from baseline in acute medication intake and disability questionnaires scores at the same timepoints. A last observation carried forward analysis was also performed., Results: A total of 90 patients who received at least one dose of fremanezumab and with a potential 12-month follow-up were included. Among them, 15 (18.0%) patients discontinued treatment for the entire population, a reduction in monthly headache days compared with baseline was reported at month 3, with a significant median [interquartile range] reduction in monthly headache days (- 9.0 [11.5], p < 0.001). A statistically different reduction was also reported at month 6 compared with baseline (- 10.0 [12.0]; p < 0.001) and at 12 months of treatment (- 10.0 [14.0]; p < 0.001). The percentage of patients with medication overuse was significantly reduced compared with baseline from 68.7% (57/83) to 29.6% (24/81), 25.3% (19/75), and 14.7% (10/68) at 3, 6, and 12 months of treatment, respectively (p < 0.001). Acute medication use (days and total number) and disability scores were also significantly reduced (p < 0.001). A ≥ 50% response rate was achieved for 51.9, 67.9, and 76.5% of all patients at 3, 6, and 12 months, respectively. Last observation carried forward analyses confirmed these findings. Fremanezumab was well tolerated, with just one patient discontinuing treatment because of adverse events., Conclusions: This study provides evidence for the real-world effectiveness of fremanezumab in treating both high-frequency episodic migraine and chronic migraine, with meaningful and sustained improvements in multiple migraine-related variables. No new safety issue was identified., (© 2023. The Author(s).)

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: 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.

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.

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.

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: Calcitonin gene-related peptide-targeted drugs have proven safe and effective for migraine prevention in large randomized-controlled, double-blind trials with an average duration of six months. Open-label studies may provide additional information on the long-term safety and efficacy of these substances., Methods: We searched PubMed for open-label trials with calcitonin gene-related peptide(-receptor) monoclonal antibodies and calcitonin gene-related peptide-receptor antagonists. We summarized and critically analyzed the literature in a narrative way., Results: Overall, 13 open-label trials were included in this review (n = 4 for erenumab, n = 4 for galcanezumab, n = 3 for fremanezumab, n = 1 for eptinezumab, n = 1 for atogepant). Open-label trial duration ranged between 12 and 264 weeks. No safety concerns emerged, and the adverse events profile was similar to the double-blind study phase. Discontinuation rates were generally low with >75% of patients remaining in the trials after one year. Efficacy data showed a sustained reduction of migraine frequency throughout the trials, along with a lasting improvement in quality of life., Conclusions: The open-label study program for calcitonin gene-related peptide-targeted migraine preventives confirms the favorable safety and efficacy profile of these drugs over time. Treatment adherence appears higher than with previous unspecific migraine preventives. Real-world data and post-marketing surveillance studies may corroborate and complement open-label results.

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.)

Objective: To critically appraise the evidence for and against premonitory symptoms in migraine being due to hypothalamic dysfunction., Discussion: Some premonitory symptoms (e.g. fatigue, mood changes, yawning, and food craving) are associated with the physiologic effects of neurotransmitters such as orexins, neuropeptide Y, and dopamine; all of which are expressed in hypothalamic neurons. In rodents, electrophysiologic recordings have shown that these neurotransmitters modulate nociceptive transmission at the level of second-order neurons in the trigeminocervical complex (TCC). Additional insights have been gained from neuroimaging studies that report hypothalamic activation during the premonitory phase of migraine. However, the available evidence is limited by methodologic issues, inconsistent reporting, and a lack of adherence to ICHD definitions of premonitory symptoms (or prodromes) in human experimental studies., Conclusions: The current trend to accept that premonitory symptoms are due to hypothalamic dysfunction might be premature. More rigorously designed studies are needed to ascertain whether the neurobiologic basis of premonitory symptoms is due to hypothalamic dysfunction or rather reflects modulatory input to the trigeminovascular system from several cortical and subcortical areas. On a final note, the available epidemiologic data raises questions as to whether the existence of premonitory symptoms and even more so a distinct premonitory phase is a true migraine phenomenon. Video recording of the debate held at the 1st International Conference on Advances in Migraine Sciences (ICAMS 2022, Copenhagen, Denmark) is available at: https://www.youtube.com/watch?v=d4Y2x0Hr4Q8 ., (© 2022. The Author(s).)

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.

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: 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.)

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).)

Background: Harmonic ratios (HRs), recurrence quantification analysis in the antero-posterior direction (RQA detAP ), and stride length coefficient of variation (CV) have recently been shown to characterize gait abnormalities and fall risk in people with Parkinson's disease (pwPD) at moderate disease stages., Research Question: This study aimed to i) assess the internal and external responsiveness to rehabilitation of HR, RQA detAP , and CV, ii) identify the baseline predictors of normalization of the gait stability indexes, and iii) investigate the correlations between the gait indexes modifications (∆) and clinical and kinematic ∆s in pwPD at Hoehn and Yahr disease staging classification 3., Methods: The trunk acceleration patterns of 21 pwPD and 21 age- and speed-matched healthy subjects (HSmatched) were acquired during gait using an inertial measurement unit at baseline (T0). pwPD were also assessed after a 4-week rehabilitation period (T1). Each participant's HR in the antero-posterior (HR AP ), medio-lateral (HR ML ), and vertical directions, RQA detAP , CV, spatio-temporal, and kinematic variables were calculated., Results: At T1, HR AP and HR ML improved to normative values and showed high internal and external responsiveness. Lower HRs and higher pelvic rotation values at baseline were predictors of ∆HRs. A minimal clinically important difference (MCID) ≥ 21.5 % is required to normalize HR AP with 95 % probability. MCID ≥ 36.9 % is required to normalize HR ML with 92 % probability. ∆HR AP correlated with ∆HR ML and both correlated with ∆stride length and ∆pelvic rotation, regardless of ∆gait speed. RQAdetAP and step length CV were not responsive to rehabilitation., Significance: When using inertial measurement units, HR AP and HR ML can be considered as responsive outcome measures for assessing the effectiveness of rehabilitation on trunk smoothness during walking in pwPD at moderate disease stages., Competing Interests: Conflict of interest statement The authors declare no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Dysphagia is a common debilitating symptom in people with Parkinson's Disease (PD), adequate screening of swallowing disorders is fundamental. The DYMUS questionnaire has shown very good characteristics for the screening of dysphagia in Multiple Sclerosis, and it might also prove useful for screening dysphagia in PD. The primary aim was to test and validate the DYMUS questionnaire in PD patients. This is an observational multicentric study involving 103 patients affected by PD. All subjects filled in the DYMUS and the Eating Assessment Tool (EAT-10) questionnaires. A subgroup of patients (n = 53) underwent a fiber-optic endoscopic evaluation of swallowing (FEES) and their dysphagia was scored by means of the Dysphagia Outcome Severity Scale (DOSS). DYMUS showed a relatively high level of internal consistency (Cronbach's alpha 0.79). A significant positive correlation was found between the DYMUS and the EAT-10 scores (p < 0.001), while a negative correlation was found between the DYMUS and the DOSS scores (p < 0.001). DYMUS showed a good sensitivity and specificity compared to FEES for detecting dysphagia (area under the curve: 0.82, p < 0.001). The ROC curve analysis showed that a DYMUS score ≥ 6 represents a reliable cut-off for the risk of dysphagia. The DYMUS questionnaire proved to be a reliable screening tool to detect dysphagia in patients suffering from PD. It is easy to understand, it can be self-administered and therefore adequate for adoption in the clinical practice with the more convenient name of DYPARK., (© 2021. The Author(s).)

We report a case of a 60-year-old patient with a 10-year history of Parkinson disease who developed a dyskinetic-dystonic gait pattern highly affecting his personal and social life. After multiple unsuccessful attempts to improve the clinical condition by adapting the pharmacologic treatment, the patient underwent gait rehabilitation based on the use of visual cueing. This approach induced a relevant improvement in the dyskinetic-dystonic gait. Our case contributes to the phenotypic description of motor fluctuations in advanced Parkinson disease and suggests an additional therapeutic option to mitigate their impact on motor performances., (© 2022 American Academy of Neurology.)

Aim: First, we investigated whether the exposure to different visual feedback conditions may modulate pain perception by means of visual induced analgesia in patients with chronic migraine. Second, to comprehend the way emotional face expressions could induce visual analgesia, we evaluated the degree of identification with the four experimental conditions., Methods: In a 1 × 4 within-subject study design, 38 female chronic migraine patients were exposed to different visual stimuli - positive face, neutral face, negative face, and control (white screen) - during a migraine attack. Visual stimuli were presented 3 times in a randomized order (each condition lasted 40 seconds). Migraine pain ratings and identification scores were assessed immediately after the observation of each visual condition., Results: We observed a significant difference in pain ratings between the positive (median: 30, 95% CI 26.69 to 38.20) and the negative (median: 30, 95% CI 33.09 to 44.13) ( z  = -4.46, p  < 0.0001) facial expressions or the neutral facial expression (median: 30, 95% CI 31.89 to 42.41) ( z  = 3.41, p  < 0.001). Participants identified more with the neutral face condition than with the other conditions., Conclusions: Observation of a positive emotional face resulted sufficient to modulate pain perception possibly via the mediation of emotion regulation for positive emotions. This study paves the way for the integration of new cognitive behavioural interventions based on the adoption of visual induced analgesia to further control pain perception in chronic migraine patients.

Purpose of Review: In this review, we illustrate and discuss the recent findings regarding the epidemiology and pathophysiology of migraine triggers and their implications in clinical practice., Recent Findings: Data from the literature suggest that individual triggers fail to provoke migraine attack in experimental settings. It is therefore possible that more triggers acting in combination are needed to induce an attack by promoting some degree of brain dysfunction and thus increasing the vulnerability to migraine. Caution is however needed, because some of the factors rated as triggers by the patients may actually be a component of the clinical picture of migraine attacks., Summary: Trigger factors of migraine are endogenous or exogenous elements associated with an increased likelihood of an attack in a short period of time and are reported by up to 75.9% of patients. Triggers must be differentiated from premonitory symptoms that precede the headache phase but do not have a causative role in attack provocation, being rather the very first manifestations of the attack. Identification of real triggers is an important step in the management of migraine. Vice versa, promoting an active avoiding behaviour toward factors whose role as triggers is not certain would be ineffective and even frustrating for patients., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The aim of this study was to determine which supervised machine learning (ML) algorithm can most accurately classify people with Parkinson's disease (pwPD) from speed-matched healthy subjects (HS) based on a selected minimum set of IMU-derived gait features. Twenty-two gait features were extrapolated from the trunk acceleration patterns of 81 pwPD and 80 HS, including spatiotemporal, pelvic kinematics, and acceleration-derived gait stability indexes. After a three-level feature selection procedure, seven gait features were considered for implementing five ML algorithms: support vector machine (SVM), artificial neural network, decision trees (DT), random forest (RF), and K-nearest neighbors. Accuracy, precision, recall, and F1 score were calculated. SVM, DT, and RF showed the best classification performances, with prediction accuracy higher than 80% on the test set. The conceptual model of approaching ML that we proposed could reduce the risk of overrepresenting multicollinear gait features in the model, reducing the risk of overfitting in the test performances while fostering the explainability of the results.

Migraine is a major neurological disorder affecting one in nine adults worldwide with a significant impact on health care and socioeconomic systems. Migraine is more prevalent in women than in men, with 17% of all women meeting the diagnostic criteria for migraine. In women, the frequency of migraine attacks shows variations over the menstrual cycle and pregnancy, and the use of combined hormonal contraception (CHC) or hormone replacement therapy (HRT) can unveil or modify migraine disease. In the general population, 18-25% of female migraineurs display a menstrual association of their headache. Here we present an overview on the evidence supporting the role of reproductive hormones, in particular estrogens, in the pathophysiology of migraine. We also analyze the efficacy and safety of prescribing exogenous estrogens as a potential treatment for menstrual-related migraine. Finally, we point to controversial issues and future research areas in the field of reproductive hormones and migraine.

Background: Pisa syndrome (PS) is a frequent postural complication of Parkinson's disease (PD). PS poorly responds to anti-parkinsonian drugs and the improvement achieved with neurorehabilitation tends to fade in 6 months or less. Transcranial direct current stimulation (t-DCS) is a non-invasive neuromodulation technique that showed promising results in improving specific symptoms in different movement disorders., Objectives: This study aimed to evaluate the role of bi-hemispheric t-DCS as an add-on to a standardized hospital rehabilitation program in the management of PS in PD., Methods: This study included 28 patients with PD and PS (21 men, aged 72.9 ± 5.1 years) who underwent a 4-week intensive neurorehabilitation treatment and were randomized to receive: i) t-DCS (t-DCS group, n = 13) for 5 daily sessions (20 min-2 mA) with bi-hemispheric stimulation over the primary motor cortex (M1), or ii) sham stimulation (sham group, n = 15) with the same duration and cadence. At baseline (T0), end of rehabilitation (T1), and 6 months later (T2) patients were evaluated with both trunk kinematic analysis and clinical scales, including UPDRS-III, Functional Independence Measure (FIM), and Numerical Rating Scale for lumbar pain., Results: When compared to the sham group, the t-DCS group achieved a more pronounced improvement in several variables: overall posture ( p = 0.014), lateral trunk inclination ( p = 0.013) during upright standing position, total range of motion of the trunk ( p = 0.012), FIM score ( p = 0.048), and lumbar pain intensity ( p = 0.017)., Conclusions: Our data support the use of neuromodulation with t-DCS as an add-on to neurorehabilitation for the treatment of patients affected by PS in PD., Competing Interests: RD, APu, MAl, MAv, CD, DM, SC, VG, MF, VB, GC, FV, GS, and EA report no funding in the preceding 12 months. APi holds grants that are not related to the subject of the present study, and he reports no biomedical financial interests or potential conflicts of interest. CT received honoraria for their participation in advisory boards or for oral presentations from Allergan, ElectroCore, Eli-Lilly, Novartis, and Teva. CT has no ownership interest and does not own stocks of any pharmaceutical company. CT serves as Chief Section Editor of Frontiers in Neurology—Section Headache Medicine and Facial Pain and on the editorial board of The Journal of Headache and Pain., (Copyright © 2022 De Icco, Putortì, Allena, Avenali, Dagna, Martinelli, Cristina, Grillo, Fresia, Bitetto, Cosentino, Valentino, Alfonsi, Sandrini, Pisani and Tassorelli.)

Introduction: The activation of perivascular fibers and the consequent release of vasoactive peptides, including the vasoactive intestinal polypeptide (VIP), play a role in migraine pathogenesis. A 2-h infusion of VIP provoked migraine, but the mechanisms remain unknown. We investigated whether 2-h infusion of VIP caused alterations in plasma levels of the calcitonin gene-related peptide (CGRP) and whether any changes might be related to the induced migraine attacks., Materials and Methods: We enrolled individuals with episodic migraine without aura and healthy participants to randomly receive a 2-h infusion of either VIP (8 pmol/kg/min) or placebo (sterile saline) in two randomized, placebo-controlled crossover trials. We collected clinical data and measured plasma levels of VIP and CGRP at fixed time points: at baseline (T 0 ) and every 30 min until 180 min (T 180 ) after the start of the infusion., Results: Blood samples were collected from patients with migraine ( n = 19) and healthy individuals ( n = 12). During VIP infusion, mixed effects analysis revealed a significant increase in plasma CGRP ( p = 0.027) at T 30 (vs. T 180 , adjusted p- value = 0.039) and T 60 (vs. T 180 , adjusted p -value = 0.027) in patients with migraine. We found no increase in plasma CGRP during VIP-induced migraine attacks ( p = 0.219). In healthy individuals, there was no increase in plasma CGRP during VIP ( p = 0.205) or placebo ( p = 0.428) days., Discussion: Plasma CGRP was elevated in patients with migraine during a prolonged infusion of VIP, but these alterations were not associated with VIP-induced migraine attacks. Given the exploratory design of our study, further investigations are needed to clarify the role of CGRP in VIP-induced migraine., Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT03989817 and NCT04260035., Competing Interests: MA reported receiving personal fees from AbbVie, Allergan, Amgen, Eli Lilly, Lundbeck, Novartis, and Teva Pharmaceuticals during the conduct of the study. MA reported serving as Associate Editor of Cephalalgia, The Journal of Headache and Pain and Brain. FA is principal investigator for a phase IV trial for Teva. FA has received personal fees for lecturing and/or participating in advisory boards for Teva, Novartis, Eli Lilly and Lundbeck. CL reported being full employee at Roche Holding AG and shareholder of Novartis International AG. JS reported being full-time employee and shareholder of Novartis International AG. MA-K reported being an invited speaker for Novartis and receiving fees from ElectroCore. JH reported receiving fees from the Danish Biotechnology Center for Cellular Communication. CL and JS were employed by Novartis Pharma AG. This study received funding from Novartis Pharma AG. The funder had the following involvement with the study: support for study design and critical revision of the manuscript., (Copyright © 2022 Pellesi, Al-Karagholi, De Icco, Chaudhry, Lopez, Snellman, Hannibal, Amin and Ashina.)

Introduction: Primary headaches represent a huge cost in terms of decreased productivity and migraine occupies the first position among disabilities in working population. Migraine has a high incidence, disproportionate to the available primary care centers. In most cases, migraine can be managed through the simple and accurate collection of clinical history, which makes it an ideal candidate for tele-healthcare., Areas Covered: In this narrative review, we retrace the most important scientific evidence regarding use of tele-healthcare in headache medicine. Over the last few years, it has proved to be a valid and useful tool for the management of migraine. Furthermore, current pandemic has imposed a drastic change in the way of thinking and setting up medicine, forcing clinicians and patients to a huge expansion of telemedicine., Expert Opinion: We should permanently insert the culture of telemedicine in the headache care not only in academies and scientific societies, but extend it to specialized hospitals for the treatment of headaches. Only by broadening the old book-based strategy, we will be able to open the door to the multidimensional culture of headache medicine. Experts of excellence centers should set an example and pave the way for the rest of the clinicians.

Background: Migraine is a complex and highly disabling neurological disease whose treatment remains challenging in many patients, even after the recent advent of the first specific-preventive drugs, namely monoclonal antibodies that target calcitonin gene-related peptide. For this reason, headache researchers are actively searching for new therapeutic targets. Cannabis has been proposed for migraine treatment, but controlled clinical studies are lacking. A major advance in cannabinoid research has been the discovery of the endocannabinoid system (ECS), which consists of receptors CB1 and CB2; their endogenous ligands, such as N-arachidonoylethanolamine; and the enzymes that catalyze endocannabinoid biosynthesis or degradation. Preclinical and clinical findings suggest a possible role for endocannabinoids and related lipids, such as palmitoylethanolamide (PEA), in migraine-related pain treatment. In animal models of migraine-related pain, endocannabinoid tone modulation via inhibition of endocannabinoid-catabolizing enzymes has been a particular focus of research., Methods: To conduct a narrative review of available data on the possible effects of cannabis, endocannabinoids, and other lipids in migraine-related pain, relevant key words were used to search the PubMed/MEDLINE database for basic and clinical studies., Results: Endocannabinoids and PEA seem to reduce trigeminal nociception by interacting with many pathways associated with migraine, suggesting a potential synergistic or similar effect., Conclusions: Modulation of the metabolic pathways of the ECS may be a basis for new migraine treatments. The multiplicity of options and the wealth of data already obtained in animal models underscore the importance of further advancing research in this area. Multiple molecules related to the ECS or to allosteric modulation of CB1 receptors have emerged as potential therapeutic targets in migraine-related pain. The complexity of the ECS calls for accurate biochemical and pharmacological characterization of any new compounds undergoing testing and development., (© 2022 American Headache Society.)

Introduction: In this open label, single-arm trial we evaluated the efficacy of onabotulinum toxin-A in the prevention of high-frequency episodic migraine (8-14 migraine days/month)., Methods: We enrolled 32 high-frequency episodic migraine subjects (age 44.8 ± 11.9 years, 11.0 ± 2.2 migraine days, 11.5 ± 2.1 headache days, 7 females). After a 28-day baseline period, subjects underwent 4 subsequent onabotulinum toxin-A treatments according to the phase III research evaluating migraine prophylaxis therapy (PREEMPT) paradigm, 12-weeks apart. The primary outcome was the reduction of monthly migraine days from baseline in the 12-week period following the last onabotulinum toxin-A treatment., Results: Onabotulinum toxin-A reduced monthly migraine days by 3.68 days (-33.1%, p < 0.01). Thirty-nine percent of the patients experienced a ≥50% reduction in monthly migraine days. Onabotulinum toxin-A also reduced the number of headache days (-33.9%, p < 0.01) and the intake of acute medications (-22.9%, p = 0.03). Disability and quality of life (QoL) scores improved markedly (migraine disability assessment (MIDAS) -41.7%; migraine specific questionnaire (MSQ) -31.7%, p < 0.01)., Conclusions: The findings suggest that, when administered according to the PREEMPT paradigm, onabotulinum toxin-A is effective in the prevention of high-frequency episodic migraine. Trial Registration: NCT04578782.