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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.

Competing Interests: RDI has received speaker honoraria for oral presentations from Eli-Lilly. CT has received fees for advisory boards or scientific lecturing from Allergan/AbbVie, Eli Lilly, Lundbeck, Novartis, and TEVA; and institutional payments for clinical trials from Allergan/AbbVie, Eli Lilly, Novartis Lundbeck, and TEVA.

Background: Monoclonal antibodies (mABs) targeting the calcitonin gene-related peptide (CGRP) pathway represent the first disease-specific preventive migraine therapy. Growing evidence suggests that they are effective in the preventive treatment of difficult-to-treat patients. In this study, we evaluated the psychological predictors of the outcome of treatment with the anti-CGRP monoclonal antibody erenumab in patients with chronic migraine (CM)., Methods: Seventy-five patients with CM who had already failed at least 3 preventive therapies received erenumab every 28 days for a period of 12 months. Before the first administration, patients received a full psychological evaluation using The Structured Clinical Interview for DSM-5 Clinician Version (SCID-5-CV) to assess personality disturbances (primary outcome), mood and anxiety disorders, and as well specific questionnaires to evaluate alexithymia traits, childhood traumas, and current stressors (secondary outcomes)., Results: After 12 months of treatment, 53 patients reported a reduction of at least 50% in headache days/per month (Responders), whereas 22 did not (Non Responders). When compared to Responders, Non Responders were characterized by a higher prevalence of personality disorders belonging to Cluster C (avoidant, dependent, and obsessive-compulsive) (77% vs 37%, p = .001). Non Responders were also characterized by a higher prevalence of anxiety disorders (90% vs 60%, p = 0.007), showed more alexithymic traits (51.7 ± 13.7 vs 42.9 ± 14.3, p = 0.017), and reported a higher number of 'at least serious' current stressors (3.2 ± 4.0 vs 0.8 ± 1.4, p < .0001) than Responders. At the multivariate analysis, higher prevalence of Cluster C personality disorders (OR 3.697; p = 0.05) and higher number of 'at least serious' life events (OR 1.382; p = 0.017) arose as prognostic factors of erenumab failure., Conclusions: Erenumab confirmed its effectiveness in a population of difficult-to-treat migraine. The presence of "anxious-fearful" personality together with current stressors and anxiety represent negative predictors of treatment outcome., Trial Registration: The study protocol was registered at clinicaltrials.gov ( NCT04361721 )., (© 2021. The Author(s).)

Background: The sequence effect (SE), defined as a reduction in amplitude of repetitive movements, is a common clinical feature of Parkinson's disease (PD) and is supposed to be a major contributor to freezing of gait (FOG). During walking, SE manifests as a step-by-step reduction in step length when approaching a turning point or gait destination, resulting in the so-called destination sequence effect (dSE). Previous studies explored the therapeutic effects of several strategies on SE, but none of them evaluated the role of an intensive rehabilitative program. Objectives: Here we aim to study the effects of a 4-week rehabilitative program on dSE in patients with PD with and without FOG. Methods: Forty-three patients (30 males, 70.6 ± 7.5 years old) with idiopathic PD were enrolled. The subjects were divided into two groups: patients with (PD + FOG, n = 23) and without FOG (PD - FOG, n = 20). All patients underwent a standardized 4-week intensive rehabilitation in-hospital program. At hospital admission (T0) and discharge (T1), all subjects were evaluated with an inertial gait analysis for dSE recording. Results: At T0, the dSE was more negative in the PD + FOG group (-0.80 ± 0.6) when compared to the PD - FOG group (-0.39 ± 0.3) ( p = 0.007), even when controlling for several clinical and demographic features. At T1, the dSE was reduced in the overall study population ( p = 0.001), with a more pronounced improvement in the PD + FOG group (T0: -0.80 ± 0.6; T1: -0.23 ± 0.4) when compared to the PD - FOG group (T0: -0.39 ± 0.3; T1: -0.22 ± 0.5) ( p = 0.012). At T1, we described in the overall study population an improvement in speed, cadence, stride duration, and stride length ( p = 0.001 for all variables). Conclusions: dSE is a core feature of PD gait dysfunction, specifically in patients with FOG. A 4-week intensive rehabilitative program improved dSE in PD patients, exerting a more notable beneficial effect in the PD + FOG group., Competing Interests: 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 holds grants and received scientific consulting fees from drug companies that are not related to the subject of the present study. The remaining 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 reviewer AS declared a shared affiliation, with no collaboration, with one of the authors MS to the handling Editor., (Copyright © 2021 Putortì, Corrado, Avenali, Martinelli, Allena, Cristina, Grillo, Martinis, Tamburin, Serrao, Pisani, Tassorelli and De Icco.)

Abstract: Migraine pathophysiology has been suggested to include dysregulation of the endocannabinoid system (ES). We simultaneously evaluated plasma anandamide (AEA) and palmitoylethanolamide (PEA) levels and spinal sensitization in a validated human model of migraine based on systemic nitroglycerin (NTG) administration. Twenty-four subjects with episodic migraine (MIG) and 19 healthy controls (HC) underwent blood sampling and investigation of nociceptive withdrawal reflex thresholds (RTh: single-stimulus threshold; TST: temporal summation threshold) before and 30 (T30), 60 (T60), and 120 (T120) minutes after sublingual NTG administration (0.9 mg). At baseline, the MIG and HC groups were comparable for plasma AEA (P = 0.822) and PEA (P = 0.182) levels, and for RTh (P = 0.142) and TST values (P = 0.150). Anandamide levels increased after NTG administration (P = 0.022) in both groups, without differences between them (P = 0.779). By contrast, after NTG administration, PEA levels increased in the MIG group at T120 (P = 0.004), while remaining stable in the HC group. Nitroglycerin administration induced central sensitization in the MIG group, which was recorded as reductions in RTh (P = 0.046) at T30 and T120, and in TST (P = 0.001) at all time points. In the HC group, we observed increases in RTh (P = 0.001) and TST (P = 0.008), which suggest the occurrence of habituation. We found no significant correlations between the ES and neurophysiological parameters. Our findings suggest a role for PEA in the ictal phase of episodic migraine. The ES does not seem to be directly involved in the modulation of NTG-induced central sensitization, which suggests that the observed PEA increase and spinal sensitization are parallel, probably unrelated, phenomena., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Background: Structural imaging has revealed changes in cortical thickness in migraine patients compared to healthy controls is reported, but presence of dynamic cortical and subcortical changes during migraine attack versus inter-ictal phase is unknown. The aim of the present study was to investigate possible changes in cortical thickness during spontaneous migraine attacks. We hypothesized that pain-related cortical area would be affected during the attack compared to an inter-ictal phase., Methods: Twenty-five patients with migraine without aura underwent three-dimensional T1-weighted imaging on a 3-Tesla MRI scanner during spontaneous and untreated migraine attacks. Subsequently, 20 patients were scanned in the inter-ictal phase, while 5 patients did not show up for the inter-ictal scan. Four patients were excluded from the analysis because of bilateral migraine pain and another one patient was excluded due to technical error in the imaging. Longitudinal image processing was done using FreeSurfer. Repeated measures ANOVA was used for statistical analysis and to control for multiple comparison the level of significance was set at p = 0.025., Results: In a total of 15 patients, we found reduced cortical thickness of the precentral (p = 0.023), pericalcarine (p = 0.024), and temporal pole (p = 0.017) cortices during the attack compared to the inter-ictal phase. Cortical volume was reduced in prefrontal (p = 0.018) and pericalcarine (p = 0.017) cortices. Hippocampus volume was increased during attack (p = 0.007). We found no correlations between the pain side or any other clinical parameters and the reduced cortical size., Conclusion: Spontaneous migraine attacks are accompanied by transient reduced cortical thickness and volume in pain-related areas. The findings constitute a fingerprint of acute pain in migraine patients, which can be used as a possible biomarker to predict antimigraine treatment effect in future studies., Trial Registration: The study was registered at ClinicalTrials.gov ( NCT02202486 )., (© 2021. The Author(s).)

Importance: Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) are structurally and functionally related, yet different in their migraine-inducing properties. It remains unclear whether the lack of migraine induction can be attributed to the only transient vasodilatory response after a 20-minute infusion of VIP., Objective: To determine whether a 2-hour infusion of VIP would provoke migraine attacks., Design, Setting, and Participants: A randomized, double-blind, placebo-controlled, crossover study was conducted between May and September 2020 at the Danish Headache Center in Copenhagen, Denmark. Patients were eligible for inclusion if they were ages 18 to 40 years, weighed between 50 and 90 kg, had a diagnosis of migraine without aura as defined by the International Classification of Headache Disorders, and had a migraine frequency of 1 to 6 attacks per month., Interventions: Patients were randomly allocated to receive a 2-hour infusion of VIP or placebo on 2 different days., Main Outcomes and Measures: The primary end point was the difference in incidence of experimentally induced migraine attacks during the observational period (0-12 hours) between VIP and placebo., Results: Twenty-one patients (17 [81%] women and 4 [19%] men; mean [range] age, 25.9 [19-40] years) were recruited in the study. Fifteen patients (71%; 95% CI, 48%-89%) developed migraine attacks after VIP compared with 1 patient (5%; 95% CI, 0%-24%) who developed a migraine attack after placebo (P < .001). The VIP-induced migraine attacks mimicked patients' spontaneous attacks. The area under the curve (AUC) of headache intensity scores (0-12 hours), as well as the AUC of the superficial temporal artery diameter (0-180 minute) were significantly greater after VIP compared with placebo (AUC0-12h, P = .003; AUC0-180min, P < .001)., Conclusions and Relevance: A 2-hour infusion of VIP caused migraine attacks, suggesting an important role of VIP in migraine pathophysiology. VIP and its receptors could be potential targets for novel migraine drugs., Trial Registration: ClinicalTrials.gov Identifier: NCT04260035.

Post-traumatic headache is a common sequela of traumatic brain injury and is classified as a secondary headache disorder. In the past 10 years, considerable progress has been made to better understand the clinical features of this disorder, generating momentum to identify effective therapies. Post-traumatic headache is increasingly being recognised as a heterogeneous headache disorder, with patients often classified into subphenotypes that might be more responsive to specific therapies. Such considerations are not accounted for in three iterations of diagnostic criteria published by the International Headache Society. The scarcity of evidence-based approaches has left clinicians to choose therapies on the basis of the primary headache phenotype (eg, migraine and tension-type headache) and that are most compatible with the clinical picture. A concerted effort is needed to address these shortcomings and should include large prospective cohort studies as well as randomised controlled trials. This approach, in turn, will result in better disease characterisation and availability of evidence-based treatment options., Competing Interests: Declaration of interests TS reports consultant fees from Eli Lilly Pharmaceuticals, Avanir Pharmaceuticals, and Neuronetrix. AJS reports personal fees from Novartis and Allergan, grants from Novartis, and grants and personal fees from Invex Therapeutics, outside of the submitted work. AIS served on an advisory board for Allergan, currently receives research support from Eli Lilly, and is an associate editor for Cephalalgia and Pain Medicine. HWS has received speaking fees from Novartis and Teva. MJL reports grants and personal fees from Eli Lilly, personal fees from Sanofi-Aventis and YuYu Pharma, and grants from Novartis, Teva, Allergan, and Yuhan, outside of the submitted work. MA is a consultant, speaker, or scientific adviser for AbbVie, Allergan, Amgen, Alder, Biohaven, Eli Lilly, Lundbeck, Novartis, and Teva; primary investigator for Alder, Amgen, Allergan, Eli Lilly, Lundbeck, Novartis, and Teva trials; has no ownership interest and does not own stocks of any pharmaceutical company; serves as an associate editor of Cephalalgia, and associate editor of the Journal of Headache and Pain; and is president of the International Headache Society. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The aims of this study were to assess the ability of 16 gait indices to identify gait instability and recurrent fallers in persons with Parkinson's disease (pwPD), regardless of age and gait speed, and to investigate their correlation with clinical and kinematic variables. The trunk acceleration patterns were acquired during the gait of 55 pwPD and 55 age-and-speed matched healthy subjects using an inertial measurement unit. We calculated the harmonic ratios (HR), percent recurrence, and percent determinism (RQAdet), coefficient of variation, normalized jerk score, and the largest Lyapunov exponent for each participant. A value of ≤1.50 for the HR in the antero-posterior direction discriminated between pwPD at Hoehn and Yahr (HY) stage 3 and healthy subjects with a 67% probability, between pwPD at HY 3 and pwPD at lower HY stages with a 73% probability, and it characterized recurrent fallers with a 77% probability. Additionally, HR in the antero-posterior direction was correlated with pelvic obliquity and rotation. RQAdet in the antero-posterior direction discriminated between pwPD and healthy subjects with 67% probability, regardless of the HY stage, and was correlated with stride duration and cadence. Therefore, HR and RQA det in the antero-posterior direction can both be used as age- and-speed-independent markers of gait instability.

Botulinum toxin type A (BoNT-A) represents a first-line treatment for spasticity, a common disabling consequence of many neurological diseases. Electrical stimulation of motor nerve endings has been reported to boost the effect of BoNT-A. To date, a wide range of stimulation protocols has been proposed in the literature. We conducted a systematic review of current literature on the protocols of electrical stimulation to boost the effect of BoNT-A injection in patients with spasticity. A systematic search using the MeSH terms "electric stimulation", "muscle spasticity" and "botulinum toxins" and strings "electric stimulation [mh] OR electrical stimulation AND muscle spasticity [mh] OR spasticity AND botulinum toxins [mh] OR botulinum toxin type A" was conducted on PubMed, Scopus, PEDro and Cochrane library electronic databases. Full-text articles written in English and published from database inception to March 2021 were included. Data on patient characteristics, electrical stimulation protocols and outcome measures were collected. This systematic review provides a complete overview of current literature on the role of electrical stimulation to boost the effect of BoNT-A injection for spasticity, together with a critical discussion on its rationale based on the neurobiology of BoNT-A uptake.

Background : Erenumab has recently been approved as a pharmacological treatment for the prevention of migraine. However, the incidence estimates of adverse drug reactions (ADRs) were not consistent among studies. Consequently, pooled measures of the incidences of ADRs that accounts for inter-study heterogeneity are desirable. In addition, little is known on the factors leading to such heterogeneity. Research design and methods : Clinical trials evaluating the occurrence of ADRs related to erenumab in migraine patients were searched with Ovid MEDLINE until April 2020. Random intercept models were used to estimate the pooled incidence of the ADRs reported at least in 5 different study populations. To examine whether specific factors correlated with the pooled incidence, we performed random-effects meta-regression. Results : Of 138 retrieved references, 8 clinical trials were included in the meta-analysis. We observed a significant heterogeneity of the incidence estimates of back pain, influenza, nasopharyngitis, and upper respiratory tract infection (URTI). Most of the observed heterogeneity is ascribed to treatment duration for back pain ( p = 0.045), influenza ( p < 0.001) and URTI ( p < 0.001), and significantly attributed to Body Mass Index (BMI) for nasopharyngitis ( p < 0.001). Conclusions : Back pain, influenza, nasopharyngitis and URTI showed a significant heterogeneity of incidence estimates.

In catastrophic situations such as pandemics, patients' healthcare including admissions to hospitals and emergency services are challenged by the risk of infection and by limitations of healthcare resources. In such a setting, the use of telemedicine interventions has become extremely important. New technologies have proved helpful in pandemics as a solution to improve the quality of life in vulnerable patients such as persons with neurological diseases. Moreover, telemedicine interventions provide at-home solutions allowing clinicians to telemonitor and assess patients remotely, thus minimizing risk of infection. After a review of different studies using telemedicine in neurological patients, we propose a telemedicine process flow for healthcare of subjects with chronic neurological disease to respond to the new challenges for delivering quality healthcare during the transformation of public and private healthcare organizations around the world forced by COVID-19 pandemic contingency. This telemedicine process flow represents a replacement for in-person treatment and thereby the provision equitable access to the care of vulnerable people. It is conceptualized as comprehensive service including (1) teleassistance with patient counseling and medical treatment, (2) telemonitoring of patients' health conditions and any changes over time, as well as (3) telerehabilitation, i.e., interventions to assess and promote body functions, activities, and consecutively participation. The hereby proposed telemedicine process flow could be adopted on a large scale to improve the public health response during healthcare crises like the COVID-19 pandemic but could equally promote equitable health care independent of people's mobility or location with respect to the specialized health care center., 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 © 2021 Matamala-Gomez, Bottiroli, Realdon, Riva, Galvagni, Platz, Sandrini, De Icco and Tassorelli.)

In this study we used nitroglycerin (NTG)-induced migraine attacks as a translational human disease model. Static and dynamic functional connectivity (FC) analyses were applied to study the associated functional brain changes. A spontaneous migraine-like attack was induced in five episodic migraine (EM) patients using a NTG challenge. Four task-free functional magnetic resonance imaging (fMRI) scans were acquired over the study: baseline, prodromal, full-blown, and recovery. Seed-based correlation analysis (SCA) was applied to fMRI data to assess static FC changes between the thalamus and the rest of the brain. Wavelet coherence analysis (WCA) was applied to test time-varying phase-coherence changes between the thalamus and salience networks (SNs). SCA results showed significantly FC changes between the right thalamus and areas involved in the pain circuits (insula, pons, cerebellum) during the prodromal phase, reaching its maximal alteration during the full-blown phase. WCA showed instead a loss of synchronisation between thalami and SN, mainly occurring during the prodrome and full-blown phases. These findings further support the idea that a temporal change in thalamic function occurs over the experimentally induced phases of NTG-induced headache in migraine patients. Correlation of FC changes with true clinical phases in spontaneous migraine would validate the utility of this model.

Inhibiting the activity of fatty-acid amide hydrolase (FAAH), the enzyme that deactivates the endocannabinoid anandamide, enhances anandamide-mediated signaling and holds promise as a molecular target for the treatment of human pathologies such as anxiety and pain. We have previously shown that the peripherally restricted FAAH inhibitor, URB937, prevents nitroglycerin-induced hyperalgesia - an animal model of migraine - and attenuates the activation of brain areas that are relevant for migraine pain, e.g. trigeminal nucleus caudalis and locus coeruleus. The current study is aimed at profiling the behavioral and biochemical effects of URB937 in animal models of acute and chronic migraine. We evaluated the effects of URB937 in two rat models that capture aspects of acute and chronic migraine, and are based on single or repeated administration of the vasodilating drug, nitroglycerin (NTG). In addition to nocifensive behavior, in trigeminal ganglia and medulla, we measured mRNA levels of neuropeptides and pro-inflammatory cytokines along with tissue levels of anandamide and palmitoylethanolamide (PEA), an endogenous agonist of peroxisome proliferator-activated receptor type-a (PPAR-a), which is also a FAAH substrate. In the acute migraine model, we also investigated the effect of subtype-selective antagonist for cannabinoid receptors 1 and 2 (AM251 and AM630, respectively) on nocifensive behavior and on levels of neuropeptides and pro-inflammatory cytokines. In the acute migraine paradigm, URB937 significantly reduced hyperalgesia in the orofacial formalin test when administered either before or after NTG. This effect was accompanied by an increase in anandamide and PEA levels in target neural tissue, depended upon CB1 receptor activation, and was associated with a decrease in calcitonin gene-related peptide (CGRP), substance P and cytokines TNF-alpha and IL-6 mRNA. Similar effects were observed in the chronic migraine paradigm, where URB937 counteracted NTG-induced trigeminal hyperalgesia and prevented the increase in neuropeptide and cytokine transcription. The results show that peripheral FAAH inhibition by URB937 effectively reduces both acute and chronic NTG-induced trigeminal hyperalgesia, likely via augmented anandamide-mediated CB1 receptor activation. These effects are associated with inhibition of neuropeptidergic and inflammatory pathways., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Little evidence is available on the role of transcranial direct current stimulation (tDCS) in patients affected by chronic migraine (CM) and medication overuse headache (MOH). We aim to investigate the effects of tDCS in patients with CM and MOH as well as its role on brain activity., Methods: Twenty patients with CM and MOH were hospitalized for a 7-day detoxification treatment. Upon admission, patients were randomly assigned to anodal tDCS or sham stimulation delivered over the primary motor cortex contralateral to the prevalent migraine pain side every day for 5 days. Clinical data were recorded at baseline (T0), after 1 month (T2) and 6 months (T3). EEG recording was performed at T0, at the end of the tDCS/Sham treatment, and at T2., Results: At T2 and T3, we found a significant reduction in monthly migraine days (p = 0.001), which were more pronounced in the tDCS group when compared to the sham group (p = 0.016). At T2, we found a significant increase of alpha rhythm in occipital leads, which was significantly higher in tDCS group when compared to sham group., Conclusions: tDCS showed adjuvant effects to detoxification in the management of patients with CM and MOH. The EEG recording showed a significant potentiation of alpha rhythm, which may represent a correlate of the underlying changes in cortico-thalamic connections., Significance: This study suggests a possible role for tDCS in the treatment of CM and MOH. The observed clinical improvement is coupled with a potentiation of EEG alpha rhythm., Competing Interests: Declaration of Competing Interest CT received honoraria for the 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. GS received honoraria for the participation in advisory boards or for oral presentations from: Eli-Lilly and Novartis. The remaining authors have no conflicts of interest., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Migraine sciences have witnessed tremendous advances in recent years. Pre-clinical and clinical experimental models have contributed significantly to provide useful insights into the brain structures that mediate migraine attacks. These models have contributed to elucidate the role of neurotransmission pathways and to identify the role of important molecules within the complex network involved in migraine pathogenesis. The contribution and efforts of several research groups from all over the world has ultimately lead to the generation of novel therapeutic approaches, specifically targeted for the prevention of migraine attacks, the monoclonal antibodies directed against calcitonin gene-related peptide or its receptor. These drugs have been validated in randomized placebo-controlled trials and are now ready to improve the lives of a large multitude of migraine sufferers. Others are in the pipeline and will soon be available.

Background: Migraine can manifest with an episodic or a chronic pattern in a continuum of disease severity. Multiple factors are associated with the progression of the pattern from episodic to chronic. One of the most consistently reported factors is the overuse of medications (MO) for the acute treatment of migraine attacks. The mechanisms through which MO facilitates the transformation of episodic migraine (EM) into chronic migraine (CM) are elusive. In order to provide insights into these mechanisms, the present study aims to identify possible peripheral biomarkers associated with the two forms of migraine, and with the presence of MO., Methods: We evaluated the plasma levels of calcitonin gene-related peptide (CGRP) and the expression of miR-34a-5p and miR-382-5p in peripheral blood mononuclear cells of subjects with EM (n = 27) or CM-MO (n = 28). Subjects in the CM-MO group were also tested 2 months after an in-hospital detoxification protocol., Results: CGRP, miR-382-5p, and miR-34a-5p levels were significantly higher in CM-MO subjects when compared to EM patients (p = 0.003 for all comparisons). After correcting for age, sex, and disease duration, miRNAs expression was still significantly associated with migraine phenotype (EM vs. CM-MO: p = 0.014 for miR-382-5p, p = 0.038 for miR-34a-5p), while CGRP levels were not (p = 0.115). CGRP plasma levels significantly and positively correlated with miR-382-5p (Spearman's rho: 0.491, p = 0.001) and miR-34a-5p (Spearman's rho: 0.303, p =0.025) in the overall population. In the CM-MO group, detoxification significantly decreased CGRP levels and miRNAs expression (p = 0.001). When comparing responders and non-responders to the detoxification, the former group (n = 23) showed significantly higher levels of CGRP at baseline, and significantly lower expression of miR-382-5p after the detoxification., Conclusions: Our findings identify a potential panel of peripheral markers associated with migraine subtypes and disease severity. CGRP levels as well as miRNAs expression were influenced by MO, and modulated by detoxification in subjects with CM-MO., Trial Registration: The study protocol was registered at www.clinicaltrials.gov ( NCT04473976 ).

Introduction: Anti-calcitonin gene-related peptide antibodies proved effective in the preventive treatment of chronic migraine. In this open label study, we aim to assess the effects of erenumab administration on neurophysiological and biomolecular profiles in a representative cohort of chronic migraine patients., Methods: Forty patients with a history of chronic migraine for at least 12 months prior to enrollment, and previous failure of at least two different preventive therapies, were enrolled. After a 1-month observation period (T0), patients were treated with erenumab 70 mg s.c. (every 28 days) for a total of three administrations. At week 12, they returned for the end-of-protocol visit (T3). At T0 and T3, patients underwent recording of clinical features, recording of single stimulus (RTh), temporal summation (TST) thresholds of the nociceptive withdrawal reflex, venous blood sampling for miR-382-5p, and miR-34a-5p quantification., Results: At T3, 31 patients (77.5%) qualified as 30% Responders (reduction in monthly migraine days by at least 30% in the last 4-week observation period). RTh (T0: 15.4 ± 8.1 mA, T3: 19.7 ± 8.2 mA) as well as TST (T0: 11.2 ± 5.8 mA, T3: 13.4 ± 5.0 mA) significantly increased at T3 in 30% Responders ( p  = 0.001 for both), while we did not observe significant changes in NON-responder patients. MiR-382-5p and miR-34a-5p levels were significantly lower after erenumab administration in the overall study population ( p  = 0.015, and p  = 0.001, respectively), without significant differences between 30% Responder and NON-responder groups., Conclusions: Different migraine phenotypes, characterized by different treatment susceptibility, may exist as suggested by the divergent behavior between neurophysiological and biomolecular findings in 30% Responder vs. NON-responder patients.The study protocol was registered at clinicaltrials.gov (NCT04361721).

Objective: To investigate reproducibility and reaction time of oropharyngeal swallowing in patients with Parkinson's disease (PD) and atypical parkinsonisms (APs)., Methods: We enrolled 19 patients with PD, 30 with APs, and 20 healthy subjects. Presence and severity of dysphagia were assessed with clinical and fiberoptic endoscopic evaluations of swallowing. Reproducibility of the oral and pharyngeal phases of swallowing were respectively assessed by calculating the 'similarity index' of the electromyography activity of the submental/suprahyoid muscles and of the laryngeal-pharyngeal mechanogram during consecutive swallows. These were performed both 'on command' and spontaneously. The swallowing reaction time was also recorded., Results: Reproducibility of the oral phase of swallowing was reduced in patients with dysphagia, mainly when swallowing 'on command'. Swallowing reaction time was prolonged in dysphagic patients. These electrophysiological parameters did not vary among different parkinsonian syndromes and correlated with dysphagia severity., Conclusions: Increased variability of oral swallowing automatisms and abnormal sensorimotor integration may be of relevance for the pathophysiology of dysphagia in parkinsonian syndromes., Significance: The electrophysiological assessment represents a valuable tool to investigate swallowing alterations in parkinsonian syndromes. It may also provide useful insights into clinical severity and pathophysiology of dysphagia, giving clues for the choice of the best therapeutic approach., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

The involvement of calcitonin gene-related peptide in migraine and cluster headache has led to the recent development of new therapies. Galcanezumab, a novel monoclonal antibody targeting the calcitonin gene-related peptide, is approved for the migraine prevention and has recently been tested for the prevention of cluster headache. Two clinical trials have been conducted to investigate the efficacy and safety of galcanezumab in episodic cluster headache and chronic cluster headache. While efficacy endpoints were not met in the chronic subtype, galcanezumab reduced the weekly frequency of attacks in patients with episodic cluster headaches. In both studies, the antibody was well tolerated. This review summarizes and critically reviews the available data regarding the rationale behind targeting the calcitonin gene-related peptide with galcanezumab for the prevention of cluster headache., Competing Interests: MMK has acted as an invited speaker for Novartis and received travel grant from ElectroCore, LLC. MA is a consultant, speaker or scientific advisor for Allergan, Amgen, Alder, ATI, Eli Lilly, Novartis, and Teva, primary investigator for Alder, Amgen, Allergan, Eli Lilly, Novartis and Teva trials. MA has no ownership interest and does not own stocks of any pharmaceutical company. MA serves as associate editor of Cephalalgia, associate editor of Headache, co-editor of the Journal of Headache and Pain. MA is President of the International Headache Society. The authors report no other conflicts of interest in this work., (© 2020 Pellesi et al.)

Background: Dysphagia in the elderly, known as presbydysphagia, has become a relevant public health problem in several countries. Swallowing disorders may be a consequence of different neurological disorders (secondary presbydysphagia) or the expression of the aging process itself (primary presbydysphagia). We aimed to test the therapeutic potential of two different non-invasive brain stimulation (NIBS) techniques in subjects with primary or secondary presbydysphagia., Methods: A blinded randomized controlled trial with crossover design was carried out in 42 patients, randomly assigned to anodal transcranial direct current stimulation (tDCS) or intermittent theta-burst stimulation (TBS) group. Both tDCS and TBS were applied for 5 consecutive days over the right swallowing motor cortex. The swallowing function was assessed before and 1 and 3 months after the stimulation using the Dysphagia Outcome and Severity Scale (DOSS), scored based on clinical assessment and fiberoptic endoscopic evaluation of swallowing. An electrophysiological method was also applied to evaluate changes in the reproducibility of the swallowing behavior., Key Results: Both real tDCS and TBS had beneficial effects on the swallowing function in patients with primary and secondary presbydysphagia. Anodal tDCS resulted in an improvement of 0.5 points in DOSS at 1-month follow-up (P = .014), whereas intermittent TBS induced an increase of 0.7 and 0.6 points at 1- and 3-month follow-up evaluations, respectively (P = .0001 and P = .005, respectively). Reproducibility of both the oral and pharyngeal phases of swallowing significantly increased at 1-month follow-up., Conclusions and Inferences: Our results suggest that non-invasive cortical stimulation may be useful for dysphagia recovery in elderly patients., (© 2020 John Wiley & Sons Ltd.)

The nitric-oxide donor nitroglycerin (NTG) administration induces a facilitation of nociceptive pathways in episodic migraine. This study aims to test the hypothesis that induced spinal sensitization could be more pronounced in patients affected by high-frequency migraine (HF-MIG) with respect to low-frequency migraine (LF-MIG). We enrolled 28 patients with LF-MIG (1-5 migraine days/month), 19 patients with HF-MIG (6-14 migraine days/month), and 21 healthy controls (HCs). Spinal sensitization was evaluated with the neurophysiological recording of the temporal summation threshold (TST) of the nociceptive withdrawal reflex at the lower limb. Temporal summation threshold was recorded at baseline and 30, 60, and 120 minutes after NTG administration (0.9 mg sublingual). Spinal sensitization was detected in LF-MIG at 60 (P = 0.010) and 120 minutes (P = 0.001) and in HF-MIG at 30 (P = 0.008), 60 (P = 0.001), and 120 minutes (P = 0.001) after NTG administration. Temporal summation threshold did not change in HC (P = 0.899). Moreover, TST reduction was more pronounced in HF-MIG with respect to LF-MIG (P = 0.002). The percentage of patients who developed a migraine-like headache after NTG was comparable in the 2 migraine groups (LF-MIG: 53.6%, HF-MIG: 52.6%, P = 0.284), whereas no subjects in the HC group developed a delayed-specific headache. Notably, the latency of headache onset was significantly shorter in the HF-MIG group when compared with the LF-MIG group (P = 0.015). Our data demonstrate a direct relationship between migraine frequency and both neurophysiological and clinical parameters, to suggest an increasing derangement of the nociceptive system control as the disease progresses, probably as a result of the interaction of genetic and environmental factors.

Introduction: Cluster Headache (CH) is a well-characterized primary headache that mostly affects men, although a progressive decrease in the male-to-female ratio has occurred over time. Available, but partly discordant, data on gender-related differences in CH suggest a more marked overlapping with migraine features in female subjects. The aim of this study is to carefully evaluate the female/male distribution of the typical migraine-associated symptoms and of other features of the disease in a large and well-characterized clinical population of CH subjects. Materials and Methods: We enrolled consecutive CH patients regularly followed at the tertiary Headache Science Center of the IRCCS Mondino Foundation of Pavia (Italy) who attended the Center for a CH bout between September 2016 and October 2018. The subjects were requested to fill in a semi-structured questionnaire focused on the presence of migraine-associated symptoms, familiarity for migraine and, for women, the relationship of CH onset with the reproductive events of their life. These data were compared and integrated with those recorded over time in our clinical database, including demographics and clinical characteristics. The primary outcome was the gender distribution of subjects who satisfied ICHD-III criterion D for migraine-associated symptoms. The secondary outcomes were represented by the gender distribution of individual migraine-associated symptoms and of other disease features included in the questionnaire and/or in the clinical database. Results: Data from 163 males (mean age 41.46 ± 10.37) and 87 females suffering of CH (mean age 42.24 ± 11.95) were analyzed. We did not find a different distribution between sexes as regards the primary outcome measure (F 73.6%, M 65.6%, p = 0.200). However, when we analyzed the occurrence of individual symptoms, nausea and osmophobia were reported more frequently by women ( p = 0.048, p = 0.037, respectively). Ptosis and nasal congestion were predominant in females ( p = 0.017 and p = 0.01, respectively), while enlarged temporal artery was more frequently reported by men ( p = 0.001). Distribution of pain across the head tended to be larger in women, extending more frequently to the zygomatic ( p = 0.050), parietal ( p = 0.049), and frontal ( p = 0.037) regions. Women had a longer mean attack duration ( p = 0.004) than men. In CH women the onset of disease often corresponded with moments of important changes in the levels of sexual hormones (menarche, post-partum, menopause). Concomitant thyroid diseases and psychiatric disorders were observed more frequently in women than in men, while snoring and smoking habit was reported by a higher percentage of men than women. Conclusion: We confirmed the presence of distinct gender-related differences in CH and added some novel information that lends credibility to the hypothesis of a closer phenotypical similarity between CH and migraine in the female sex. These observations are relevant for advancing our knowledge on CH pathophysiology, as well as for a more refined diagnostic framing and improved management of the disease., (Copyright © 2019 Allena, De Icco, Sances, Ahmad, Putortì, Pucci, Greco and Tassorelli.)

Background: Circadian dysfunction is thought to take part in the pathogenesis of sleep disorders in Alzheimer's disease (AD) and in AD pathophysiology itself., Objective: Our study aims to calculate dim light melatonin onset (DLMO) secretion in order to define the circadian phase in patients with AD at an early stage of the disease., Methods: Twenty-one patients (M/F: 11/10; mean age 74.1 ± 5.4 years; mean disease duration 3.4 ± 1.6 years) with a diagnosis of AD and 17 healthy controls (HC; M/F: 10/7; mean age 67.47 ± 3.8 years) were investigated for subjective nocturnal sleep quality and chronotype, for DLMO and quantitative aspects of the evening melatonin secretion by means of a 5-point in-home evening melatonin saliva test., Results: Subjective sleep quality score on the Pittsburgh Sleep Quality Index questionnaire (PSQI) above 5 (p = 0.24), insomnia frequency as measured by Sleep Condition Indicator Questionnaire (p = 0.823) and the subjective chronotype according to Morning Evening Questionnaire (MEQ) scores distribution (p = 0.464) did not differ between AD and HC. However, DLMO occurred significantly later (55 min; p = 0.028), and melatonin secretion following DLMO was significantly decreased in AD patients compared to HC., Conclusion: Initial evening secretion of melatonin proves to be delayed and mildly impaired in patients with a mild/moderate form of Alzheimer disease while patients' subjective sleep parameters and chronotype are reported to be similar to those of HC. These results indicate that subclinical altered patterns of melatonin secretion occur in subjects with AD at an early stage of the disease., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The International Classification of Headache Disorders lists different subtypes of medication overuse headache (MOH), according to the medication overused. The aim of this study is to evaluate whether the different subtypes correspond to clinically distinguishable phenotypes in a large population., Method: This descriptive cross-sectional observational study included 660 patients with MOH referred to headache centers in Europe and Latin America as a part of the COMOESTAS project. Information about clinical features was collected with structured patient interviews and with self-administered questionnaires for measuring disability, anxiety, and depression., Results: Female/male ratio, body mass index, marital status, and level of education were similar among in subjects enrolled in the 5 centers. The mean age was higher among subjects overusing triptans (T-MOH) with respect to subjects overusing simple analgesic (A-MOH). Duration of headache before chronification was longer in T-MOH (19.2 ± 11.9 years) and in subjects overusing ergotamines (E-MOH, 17.8 ± 11.7 years) with respect to the A-MOH group (13.1 ± 10.9; P < .001 and P = .017, respectively) and in T-MOH with respect multiple drug classes (M-MOH, 14.9 ± 11.7; P = .030). Migraine Disability Assessment (MIDAS) score was significantly lower in E-MOH group (33.6 ± 41.6), while T-MOH group (56.8 ± 40.6) had a significant lower MIDAS score with respect to M-MOH (67.2 ± 62.5; P = .016 and P = .037, respectively). Prevalence of depression and anxiety was lower in patients overusing T with respect to other groups of patients (χ 2  = 10.953, P = .027 and χ 2  = 25.725, P < .001, respectively)., Conclusion: In this study on a large and very well characterized population of MOH, we describe the distinctive clinical characteristics of MOH subtypes. These findings contribute to more clearly define the clinical picture of a poorly delineated headache disorder. They also provide some insights in the possible trajectories leading to this highly disabling chronic headache, that is classified as a secondary form, but whose occurrence is entirely dependent on an underlying primary headache., (© 2019 American Headache Society.)

Spasticity is a muscle tone disorder associated with different neurological conditions. Spasticity could be associated with pain, high disability, poor functional recovery, and reduced quality of life. Botulinum neurotoxin type A (BoNT-A) is considered a first-line treatment for spasticity and, more recently, it also represents a therapeutic option for various chronic pain conditions. In this open label study, we aim to evaluate the effect of the BoNT-A on the spinal nociception in patients affected by spasticity of the lower limbs with associated pain with predominantly neuropathic features. Ten patients with stroke, 10 with multiple sclerosis and 5 with spinal cord injury were enrolled in the study. They were tested with clinical scales (neuropathic pain scale inventory (NPSI), numerical rating scale (NRS), modified Ashworth scale (MAS) and with the nociceptive withdrawal reflex at lower limbs to explore the spinal temporal summation threshold at baseline and 30 day after BoNT-A injection. OnabotulinumtoxinA (50 to 200 units per site) was injected in the lower limb muscles according to the distribution of spasticity. No significant differences were found at baseline for neurophysiological features across groups. After the BoNT-A injection, we recorded a significant reduction in MAS and NRS scores. Regarding the neurophysiological parameters, we described a significant increase in the temporal summation threshold after the BoNT-A injection. Our data supports the hypothesis that peripherally injected OnabotulinumtoxinA modulates the excitability of spinal cord nociceptive pathways. This activity may take place irrespective of the effect of the drug on spasticity.

Migraine is a disease for which there is still no defined pathophysiological etiology and few translational models. The organic nitrate nitroglycerin has been in use as an experimental model of migraine in both human and animal studies for several years. The drug produces a number of effects within the head, that includes blood vessels, nerves and brain areas that may produce a response similar to a migraine attack in predisposed subjects. A better understanding of the nature of these changes and how well they parallel a true migraine attack would allow for a translational model to better understand some of the mechanisms involved in the generation of a migraine attack. The present review summarizes the known body of knowledge of nitroglycerin effects evaluated in humans and animals as it relates to potential mechanisms associated with migraine headaches., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Early traumatic experiences and Stressful episodes appear to be associated to the development and perpetuation of chronic pain disorders and to dependence-related behaviors. Objective: The present study evaluated whether these factors can be predictors, together with psychiatric conditions, of the outcome of a detoxification treatment in patients suffering from chronic migraine and medication-overuse headache in a 2-month follow-up. Methods: Consecutive patients undergoing a detoxification program as therapy for treating chronic migraine and medication overuse headache at the Pavia Headache Center were analyzed. During this program, lasting about 1 week, all patients received the standard CARE in-patient withdrawal protocol, which consisted in discontinuing abruptly the overused drug(s) and receiving daily detoxification therapy. Data on childhood traumatic events and recent stressful ones were analyzed by means of the Childhood Trauma Questionnaire and Stressful life-events Questionnaire. Psychiatric conditions were evaluated using the Structured Clinical Interview for Diagnostic and Statistical Manual of mental disorders. Results: A total of 166 (80% females; mean age 44.7) patients completed the follow-up at 2 months after the detoxification program: of these 118 (71%) (78% females; mean age 44.7) stopped overuse and reverted to an episodic pattern of headache (Group A); 19 (11%) (89% females; mean age 41.3) kept overusing and maintained a chronic pattern of headache (Group B); and 29 (18%) (79% females; mean age 46.9) stopped overuse without any benefit on headache frequency (Group C). At the multivariate analyses, a higher number of early life emotional distress (Odds Ratio 11.096; p = 0.037) arose as a prognostic factor for the outcome in Group B, while major depression during life-time (Odds Ratio 3.703; p = 0.006) and higher number of severe stressful episodes in the past 10 years (Odds Ratio 1.679; p = 0.045) were prognostic factors for the outcome of Group C. Conclusions: Data suggest that early life traumas and stressful events have a negative impact on the outcome of the detoxification program in subjects overusing acute medication for headache. The history of emotional childhood traumas is associated to the failure to cease overuse, whereas recent very serious life events are associated to the persistence of headache chronicity.

Background: Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can improve detection of CM and alleviate its significant societal burden. We aimed to develop and validate the Italian version of the ID-CM (ID-EC) in paper and as a smart app version in a headache clinic-based setting., Methods: The study investigators translated and adapted to the Italian language the original ID-CM questionnaire (ID-EC) and further implemented it as a smart app. The ID-EC was tested in its paper and electronic version in consecutive patients referring to 9 Italian tertiary headache centers for their first in-person visit. The scoring algorithm of the ID-EC paper version was applied by the study investigators (case-finding) and by patients (self-diagnosis), while the smart app provided to patients automatically the diagnosis. Diagnostic accuracy of the ID-EC was assessed by matching the questionnaire results with the interview-based diagnoses performed by the headache specialists during the visit according to the criteria of International Classification of Headache Disorders, III edition, beta version., Results: We enrolled 531 patients in the test of the paper version of ID-EC and 427 in the validation study of the smart app. According to the clinical diagnosis 209 patients had CM in the paper version study and 202 had CM in the smart app study. 79.5% of patients returned valid paper questionnaires, while 100% of patients returned valid and complete smart app questionnaires. The paper questionnaire had a 81.5% sensitivity and a 81.1% specificity for case-finding and a 30.7% sensitivity and 90.7% specificity for self-diagnosis, while the smart app had a 64.9% sensitivity and 90.2% specificity., Conclusions: Our data suggest that the ID-EC, developed and validated in tertiary headache centers, is a valid case-finding tool for CM, with sensitivity and specificity values above 80% in paper form, while the ID-EC smart app is more useful to exclude CM diagnosis in case of a negative result. Further studies are warranted to assess the diagnostic accuracy of the ID-EC in general practice and population-based settings.

Background : Central neuropathic pain represents one of the most common symptoms in multiple sclerosis (MS) and it seriously affects quality of life. Spinal mechanisms may contribute to the pathogenesis of neuropathic pain in MS. Converging evidence from animal models and neurophysiological and clinical studies in humans suggests a potential effect of transcranial direct current stimulation (tc-DCS) on neuropathic pain. Spinal application of DCS, i.e., transcutaneous spinal DCS (ts-DCS), may modulate nociception through inhibition of spinal reflexes. Therefore, ts-DCS could represents an effective, safe and well-tolerated treatment for neuropathic pain in MS, a largely unexplored topic. This study is a pilot randomized double-blind sham-controlled trial to evaluate the efficacy of ts-DCS on central neuropathic pain in MS patients. Methods : Thirty-three MS patients with central neuropathic pain were enrolled and randomly assigned to two groups in a double-blind sham-controlled design: anodal ts-DCS group ( n = 19, 10 daily 20-min sessions, 2 mA) or sham ts-DCS group ( n = 14, 10 daily 20-min sessions, 0 mA). The following clinical outcomes were evaluated before ts-DCS treatment (T0), after 10 days of treatment (T1) and 1 month after the end of treatment (T2): neuropathic pain symptoms inventory (NPSI), Ashworth Scale (AS) for spasticity and Fatigue Severity Scale (FSS). A subgroup of patients treated with anodal ts-DCS ( n = 12) and sham ts-DCS ( n = 11) also underwent a parallel neurophysiological study of the nociceptive withdrawal reflex (NWR) and the NWR temporal summation threshold (TST), two objective markers of pain processing at spinal level. Results : Anodal ts-DCS group showed a significant improvement in NPSI at T1, which persisted at T2, while we did not detect any significant change in AS and FSS. Sham ts-DCS group did not show any significant change in clinical scales. We observed a non-significant trend towards an inhibition of NWR responses in the anodal ts-DCS group at T1 and T2 when compared to baseline. Conclusions : Anodal ts-DCS seems to have an early and persisting (i.e., 1 month after treatment) clinical efficacy on central neuropathic pain in MS patients, probably through modulation of spinal nociception. Clinical Trial Registration: www.ClinicalTrials.gov, identifier #NCT02331654.

Aim: To identify factors that may be predictors of the outcome of a detoxification treatment in medication-overuse headache., Methods: Consecutive patients entering a detoxification program in six centres in Europe and Latin America were evaluated and followed up for 6 months. We evaluated anxious and depressive symptomatology (though patients with severe psychiatric comorbidity were excluded), quality of life, headache-related disability, headache characteristics, and prophylaxis upon discharge., Results: Of the 492 patients who completed the six-month follow up, 407 ceased overuse following the detoxification (non overusers), another 23 ceased overuse following detoxification but relapsed during the follow-up. In the 407 non-overusers, headache acquired an episodic pattern in 287 subjects (responders). At the multivariate analyses, lower depression scores (odds ratio = 0.891; p = 0.001) predicted ceasing overuse. The primary headache diagnosis - migraine with respect to tension-type headache (odds ratio = 0.224; p = 0.001) or migraine plus tension-type headache (odds ratio = 0.467; p = 0.002) - and the preventive treatment with flunarizine (compared to no such treatment) (odds ratio = 0.891; p = 0.001) predicted being a responder. A longer duration of chronic headache (odds ratio = 1.053; p = 0.032) predicted relapse into overuse. Quality of life and disability were not associated with any of the outcomes., Conclusions: Though exploratory in nature, these findings point to specific factors that are associated with a positive outcome of medication-overuse headache management, while identifying others that may be associated with a negative outcome. Evaluation of the presence/absence of these factors may help to optimize the management of this challenging groups of chronic headache sufferers.

Focal dystonia is characterized by involuntary muscle contractions that cause abnormal postures and/or twisting movements in a segment of the body. Motor symptoms have a major impact on disability in this condition, but the presence of pain represents an additional source of impairment and poor quality of life. Notwithstanding that pain occurs in up to 70% of patients with cervical dystonia and in a relevant proportion of subjects with focal dystonia of the limbs, it has received very little attention from researchers and controlled trials are scant. The aim of this review is to summarize the current knowledge on the clinical assessment and management of pain in focal dystonias. The search results will inform on the types of pain reported in focal dystonias, on the tools that are used to quantify pain and on the efficacy of pharmacological and non-pharmacological approaches. The collated data will hopefully improve the clinical management of focal dystonia and also stimulate future research on dystonia-associated pain. Optimization of the outcome indeed requires the identification and the management of all the factors that determine disability and hence relies on a multidisciplinary approach., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction The mechanism of action of non-invasive vagal nerve stimulation in the treatment of migraine is elusive. We studied its effect in a human model of pain, the nociceptive withdrawal reflex. Methods We enrolled 10 healthy subjects who underwent active non-invasive vagal nerve stimulation and sham treatment in a randomized, cross-over, sham-controlled study. Non-invasive vagal nerve stimulation was delivered with gammaCore®. The assessment of the nociceptive withdrawal reflex was performed at baseline (T0) and at 5 (T5) and 30 (T30) minutes after stimulation. Results Non-invasive vagal nerve stimulation significantly increased the reflex threshold to single stimulus at both T5 and T30 and the temporal summation threshold at T30. Sham treatment did not modify any parameters. Discussion These findings are consistent with a modulation of central descending pathways for pain control. An altered spinal and supraspinal control of pain has been described in primary headache, so this effect may partially explain the therapeutic effect of non-invasive vagal nerve stimulation.

We investigated whether the stimulation frequency (SF), the pain phases, and different diagnoses of trigeminal autonomic cephalalgias (TACs) may influence the habituation to pain. We studied the habituation of the nociceptive blink reflex R2 responses at different SFs (.05, .1, .2, .3, .5, and 1 Hz), in 28 episodic cluster headache (ECH) patients, 16 during and 12 outside the bout; they were compared with 16 episodic paroxysmal hemicrania (EPH) during the bout and 21 healthy subjects. We delivered 26 electrical stimuli and subdivided stimuli 2 to 26 in 5 blocks of 5 responses for each SF. Habituation values for each SF were expressed as the percentages of the mean area value of second through fifth blocks with respect to the first one. A significant lower mean percentage decrease of the R2 area across all blocks was found at .2 to 1 Hz SF during ECH, outside of the ECH, and EPH compared with healthy subjects. We showed a common frequency-dependent deficit of habituation of trigeminal nociceptive responses at higher SFs in ECH and EPH patients, independently from the disease phase. This abnormal temporal pattern of pain processing may suggest a trait-dependent dysfunction of some underlying pain-related subcortical structures, rather than a state-dependent functional abnormality due to the recurrence of the headache attacks during the active period., Perspective: TACs showed a frequency-related defective habituation of nociceptive trigeminal responses at the higher SFs, irrespectively of the diagnosis and/or the disease phase. We showed that the clinical similarities in the different subtypes of TACs are in parallel with a trait-dependent dysfunction in pain processing., (Copyright © 2018 The American Pain Society. Published by Elsevier Inc. All rights reserved.)

OnabotulinumtoxinA has been approved for the prophylaxis of chronic migraine following the demonstration of efficacy in two large controlled trials. Data collected from pragmatic studies in the real-life setting have contributed important additional information useful for the management of this group of extremely disabled and challenging patients. The main findings from these studies are presented and discussed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)