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Transcranial magnetic stimulation-evoked electroencephalography potentials (TEPs) have been used to study motor cortical excitability in healthy subjects and several neurological conditions. However, optimal recording parameters for TEPs are still debated. Stimulation rates could affect TEP amplitude due to plasticity effects, thus confounding the assessment of cortical excitability. We tested whether short interpulse intervals (IPIs) affect TEP amplitude.

Background: Fatigue, depression and slow processing speed are debilitating symptoms in people with Relapsing-Remitting Multiple Sclerosis (RRMS) that significantly impacts on the quality of life. Natalizumab, a disease-modifying treatment, improves clinical symptoms but questions remain about the comparative efficacy between its standard interval dosing (SID) and extended interval dosing (EID) schedules., Objective: To examine the impact of short term natalizumab dosing schedules-SID versus EID-on the so called "invisible symptoms", specifically focusing on symptom exacerbation during the 'wearing-off' phase before infusion and the subsequent relief post-infusion., Methods: Forty-two RRMS patients were assessed one week before (T0) and two weeks after pre-and post-natalizumab infusion (T1) for fatigue symptoms using the Fatigue Scale for Motor and Cognitive Functions (FSMC), the Modified Fatigue Impact Scale (MFIS), and the Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS). Processing speed and depression were measured by the symbol digit modality test (SDMT), and the Beck Depression Inventory-II (BDI-II). Participants were categorized into either the SID or EID dosing schedules of natalizumab, and their outcomes were compared., Results: Forty-two patients (21 SID; 21 EID) completed the study. Fatigue severity scales, SDMT, and BDI-II scores improved from T0 to T1. No significant differences in fatigue symptoms were found between the SID and EID groups, whether during the "wearing-off" period (T0) or post-infusion (T1)., Conclusions: Both SID and EID dosing regimens of natalizumab are similarly effective in reducing fatigue symptoms, depression and improving processing speed in individuals with RRMS, with no observed differences during the "wearing-off" periods or after re-infusion., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Antonella Conte reports financial support was provided by Biogen Inc. Antonella Conte reports financial support was provided by Italian Ministry of Health. Antonella Conte reports a relationship with Roche that includes: funding grants and speaking and lecture fees. Antonella Conte reports a relationship with Sanofi that includes: funding grants and speaking and lecture fees. Antonella Conte reports a relationship with Almirall that includes: speaking and lecture fees. Antonella Conte reports a relationship with Bristol Myers Squibb Co that includes: speaking and lecture fees. Antonella Conte reports a relationship with Merck & Co Inc that includes: speaking and lecture fees. Antonella Conte reports a relationship with Novartis that includes: speaking and lecture fees. Carlo Pozzilli reports a relationship with Hoffmann-La Roche Limited that includes: consulting or advisory. Carlo Pozzilli reports a relationship with Merck that includes: consulting or advisory and speaking and lecture fees. Carlo Pozzilli reports a relationship with Novartis that includes: consulting or advisory and speaking and lecture fees. Carlo Pozzilli reports a relationship with Janssen that includes: consulting or advisory and speaking and lecture fees. Carlo Pozzilli reports a relationship with Almirall that includes: consulting or advisory and speaking and lecture fees. Carlo Pozzilli reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory and speaking and lecture fees. Carlo Pozzilli reports a relationship with Alexion that includes: consulting or advisory and speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Giorgio Leodori has nothing to declare, Marco Mancuso has nothing to declare, Davide Maccarrone has nothing to declare, Matteo Tartaglia has nothing to declare, Antonio Ianniello has nothing to declare, Viola Baione has nothing to declare, Gina Ferrazzano has nothing to declare, Leonardo Malimpensa has nothing to declare, Daniele Belvisi has nothing to declare, Alfredo Berardelli has nothing to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Substantial evidence highlights the role of the cerebellum in the pathophysiology of tremor in essential tremor (ET), although its potential involvement in altered movement execution in this condition remains unclear. This study aims to explore potential correlations between the cerebellum and basal ganglia functional connectivity and voluntary movement execution abnormalities in ET, objectively assessed with kinematic techniques. A total of 20 patients diagnosed with ET and 18 healthy subjects were enrolled in this study. Tremor and repetitive finger tapping were recorded using an optoelectronic kinematic system. All participants underwent comprehensive 3T-MRI examinations, including 3D-T1 and blood-oxygen-level dependent (BOLD) sequences during resting state. Morphometric analysis was conducted on the 3D-T1 images, while a seed-based analysis was performed to investigate the resting-state functional connectivity (rsFC) of dorsal and ventral portions of the dentate nucleus and the external and internal segments of the globus pallidus. Finally, potential correlations between rsFC alterations in patients and clinical as well as kinematic scores were assessed. Finger tapping movements were slower in ET than in healthy subjects. Compared to healthy subjects, patients with ET exhibited altered FC of both dentate and globus pallidus with cerebellar, basal ganglia, and cortical areas. Interestingly, both dentate and pallidal FC exhibited positive correlations with movement velocity in patients, differently from that we observed in healthy subjects, indicating the higher the FC, the faster the finger tapping. The findings of this study indicate the possible role of both cerebellum and basal ganglia in the pathophysiology of altered voluntary movement execution in patients with ET., (© 2024. The Author(s).)

Multiple sclerosis (MS) is a debilitating neurological disease that has been classified as an immune-mediated attack on myelin, the protective sheath of nerves. Some aspects of its pathogenesis are still unclear; nevertheless, it is generally established that viral infections influence the course of the disease. Cytomegalovirus (CMV) is a major pathogen involved in alterations of the immune system, including the expansion of highly differentiated cytotoxic CD8+ T cells and the accumulation of adaptive natural killer (NK) cells expressing high levels of the NKG2C receptor. In this study, we evaluated the impact of latent CMV infection on MS patients through the characterization of peripheral NK cells, CD8+ T cells, and NKT-like cells using flow cytometry. We evaluated the associations between immune cell profiles and clinical features such as MS duration and MS progression, evaluated using the Expanded Disability Status Scale (EDSS). We showed that NK cells, CD8+ T cells, and NKT-like cells had an altered phenotype in CMV-infected MS patients and displayed high levels of the NKG2C receptor. Moreover, in MS patients, increased NKG2C expression levels were found to be associated with higher EDSS scores. Overall, these results support the hypothesis that CMV infection imprints the immune system by modifying the phenotype and receptor repertoire of NK and CD8+ T cells, suggesting a detrimental role of CMV on MS progression.

Motor fatigue is one of the most common symptoms in multiple sclerosis (MS) patients. Previous studies suggested that increased motor fatigue in MS may arise at the central nervous system level. However, the mechanisms underlying central motor fatigue in MS are still unclear. This paper investigated whether central motor fatigue in MS reflects impaired corticospinal transmission or suboptimal primary motor cortex (M1) output (supraspinal fatigue). Furthermore, we sought to identify whether central motor fatigue is associated with abnormal M1 excitability and connectivity within the sensorimotor network. Twenty-two patients affected by relapsing-remitting MS and 15 healthy controls (HCs) performed repeated blocks of contraction at different percentages of maximal voluntary contraction with the right first dorsal interosseus muscle until exhaustion. Peripheral, central, and supraspinal components of motor fatigue were quantified by a neuromuscular assessment based on the superimposed twitch evoked by peripheral nerve and transcranial magnetic stimulation (TMS). Corticospinal transmission, excitability and inhibition during the task were tested by measurement of motor evoked potential (MEP) latency, amplitude, and cortical silent period (CSP). M1 excitability and connectivity was measured by TMS-evoked electroencephalography (EEG) potentials (TEPs) elicited by M1 stimulation before and after the task. Patients completed fewer blocks of contraction and showed higher values of central and supraspinal fatigue than HCs. We found no MEP or CSP differences between MS patients and HCs. Patients showed a post-fatigue increase in TEPs propagation from M1 to the rest of the cortex and in source-reconstructed activity within the sensorimotor network, in contrast to the reduction observed in HCs. Post-fatigue increase in source-reconstructed TEPs correlated with supraspinal fatigue values. To conclude, MS-related motor fatigue is caused by central mechanisms related explicitly to suboptimal M1 output rather than impaired corticospinal transmission. Furthermore, by adopting a TMS-EEG approach, we proved that suboptimal M1 output in MS patients is associated with abnormal task-related modulation of M1 connectivity within the sensorimotor network. Our findings shed new light on the central mechanisms of motor fatigue in MS by highlighting a possible role of abnormal sensorimotor network dynamics. These novel results may point to new therapeutical targets for fatigue in MS., Competing Interests: Declaration of Competing Interest The authors report no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Timely diagnosis of secondary progressive multiple sclerosis (SPMS) represents a clinical challenge. The Frailty Index, a quantitative frailty measure, and the Neurophysiological Index, a combined measure of sensorimotor cortex inhibitory mechanism parameters, have recently emerged as promising tools to support SPMS diagnosis. The aim of this study was to explore the possible relationship between these two indices in MS. MS participants underwent a clinical evaluation, Frailty Index administration, and neurophysiological assessment. Frailty and Neurophysiological Index scores were found to be higher in SPMS and correlated with each other, thus suggesting that they may capture similar SPMS-related pathophysiological mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tartaglia, Canevelli, Malimpensa, Belvisi, Baione, Ferrazzano, Leodori, Berardelli and Conte.)

Background: The mRNA vaccines help protect from COVID-19 severity, however multiple sclerosis (MS) disease modifying therapies (DMTs) might affect the development of humoral and T-cell specific response to vaccination., Methods: The aim of the study was to evaluate humoral and specific T-cell response, as well as B-cell activation and survival factors, in people with MS (pwMS) under DMTs before (T0) and after two months (T1) from the third dose of vaccine, comparing the obtained findings to healthy donors (HD). All possible combinations of intracellular IFNγ, IL2 and TNFα T-cell production were evaluated, and T-cells were labelled "responding T-cells", those cells that produced at least one of the three cytokines of interest, and "triple positive T-cells", those cells that produced simultaneously all the three cytokines., Results: The cross-sectional evaluation showed no significant differences in anti-S antibody titers between pwMS and HD at both time-points. In pwMS, lower percentages of responding T-cells at T0 (CD4: p=0.0165; CD8: p=0.0022) and triple positive T-cells at both time-points compared to HD were observed (at T0, CD4: p=0.0007 and CD8: p=0.0703; at T1, CD4: p=0.0422 and CD8: p=0.0535). At T0, pwMS showed higher plasma levels of APRIL, BAFF and CD40L compared to HD (p<0.0001, p<0.0001 and p<0.0001, respectively) and at T1, plasma levels of BAFF were still higher in pwMS compared to HD (p=0.0022).According to DMTs, at both T0 and T1, lower anti-S antibody titers in the depleting/sequestering-out compared to the enriching-in pwMS subgroup were found (p=0.0410 and p=0.0047, respectively) as well as lower percentages of responding CD4+ T-cells (CD4: p=0.0394 and p=0.0004, respectively). Moreover, the depleting/sequestering-out subgroup showed higher percentages of IFNγ-IL2-TNFα+ T-cells at both time-points, compared to the enriching-in subgroup in which a more heterogeneous cytokine profile was observed (at T0 CD4: p=0.0187; at T0 and T1 CD8: p =0.0007 and p =0.0077, respectively)., Conclusion: In pwMS, humoral and T-cell response to vaccination seems to be influenced by the different DMTs. pwMS under depleting/sequestering-out treatment can mount cellular responses even in the presence of a low positive humoral response, although the cellular response seems qualitatively inferior compared to HD. An understanding of T-cell quality dynamic is needed to determine the best vaccination strategy and in general the capability of immune response in pwMS under different DMT., 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 Dominelli, Zingaropoli, Tartaglia, Tortellini, Guardiani, Perri, Pasculli, Ciccone, Malimpensa, Baione, Napoli, Gaeta, Lichtner, Conte, Mastroianni and Ciardi.)

Introduction: The Health Assessment Questionnaire (HAQ) has been translated into many languages and it has been classified as the predictor of disability and medical costs, however, the psychometric properties of the HAQ have never been studied in a population with neurological disease. The purpose of this study was the evaluation of the psychometric properties of HAQ in a population of individuals with multiple sclerosis (MS)., Materials and Methods: This cross-sectional study was conducted with patients diagnosed with MS. The evaluation tools administered were the 36-item short form health survey (SF-36) to evaluate the health state of the patients and HAQ and to evaluate the limitations of the activities of daily living (ADL)., Results: A total of 34 patients were included in this study. Cronbach's alpha assessed the internal consistency of the HAQ, and it is equal to 0.94. The study revealed some significant correlations between the dimensions of the SF-36 and the sub-categories of the HAQ using Pearson's Correlation Coefficient. Significant correlations emerged between the demographic and clinical characteristics of patients and the subcategories of HAQ., Discussion: The HAQ is a valid and reliable tool to assess the limitations of the activities of daily living, and it could provide for the healthcare and rehabilitation sector with an additional evaluation tool., 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 Berardi, Conte, Cimmino, Cimmino, Baione, Crisafulli, Tofani, Tartaglia, Fabbrini and Galeoto.)

Introduction: The Jebsen Taylor Hand Function Test (JTHFT) is a non-diagnostic assessment scale for hand and upper limb dexterity that is commonly used in various countries around the world for diseases, such as muscular dystrophy, stroke, spinal cord injury, Parkinson, carpal tunnel syndrome, and rheumatoid arthritis. This study aimed to evaluate the psychometric properties of the JTHFT in Italian adults with Multiple Sclerosis (MS)., Materials and Methods: The test's internal consistency was evaluated with Cronbach's alpha, whereas its concurrent validity was evaluated by comparing the JTHFT with the Health Assessment Questionnaire (HAQ) and by calculating Pearson's correlation coefficient., Results: The JTHFT was administered to 29 Italians with MS. The Cronbach's alpha showed that the nondominant hand has a value of 0.76 and 0.91 for the dominant hand. Pearson's correlation coefficient showed significant correlations between JTHFT and HAQ., Discussion: The JTHFT is a reliable tool to evaluate the functionality of the upper limb and hand in patients with MS. This tool is useful for testing the effectiveness of a treatment in various diseases. The results obtained in this study are coherent with previous studies that are conducted in populations with different diseases. In particular, the correlation between JTHFT and HAQ showed that a disability related to the upper limbs can often have repercussions, not only on activities of daily living, but also on walking. Based on this correlation, the motor deficits that emerged may be linked to a brain marrow disease rather than a spinal disease, even if an essential deepening can confirm this hypothesis., 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 Berardi, Galeoto, Pasquali, Baione, Crisafulli, Tofani, Tartaglia, Fabbrini and Conte.)

Secondary progressive multiple sclerosis (SPMS) subtype is retrospectively diagnosed, and biomarkers of the SPMS are not available. We aimed to identify possible neurophysiological markers exploring grey matter structures that could be used in clinical practice to better identify SPMS. Fifty-five people with MS and 31 healthy controls underwent a transcranial magnetic stimulation protocol to test intracortical interneuron excitability in the primary motor cortex and somatosensory temporal discrimination threshold (STDT) to test sensory function encoded in cortical and deep grey matter nuclei. A logistic regression model was used to identify a combined neurophysiological index associated with the SP subtype. We observed that short intracortical inhibition (SICI) and STDT were the only variables that differentiated the RR from the SP subtype. The logistic regression model provided a formula to compute the probability of a subject being assigned to an SP subtype based on age and combined SICI and STDT values. While only STDT correlated with disability level at baseline evaluation, both SICI and STDT were associated with disability at follow-up. SICI and STDT abnormalities reflect age-dependent grey matter neurodegenerative processes that likely play a role in SPMS pathophysiology and may represent easily accessible neurophysiological biomarkers for the SPMS subtype.

Background: The disease-modifying therapies (DMTs) largely used in multiple sclerosis (MS) may result in higher infectious risk., Objective: We aimed to investigate the infectious risk in DMT-treated MS patients., Methods: MS patients were evaluated for infectious risk before starting, switching or during DMT., Results: In this three-year observational cohort study 174 MS patients were enrolled. Among them, 18 patients were anti-HBc + and 19 patients were QuantiFERON®-TB Gold In-Tube (QFT)  +  . No patients with anti-HBc + showed a detectable HBV-DNA and all started DMT. Among QTB + patients, 17 latent TB infections (LTBIs) and 2 active TB infections (TBIs) were identified. After one month of LTBI prophylaxis or TB treatment, respectively, all patients started DMTs.Overall, 149 started DMTs. During DMTs, one ocrelizumab-treated patient with anti-HBc + developed HBV reactivation and six patients (3 on natalizumab, 2 on ocrelizumab and 1 on IFN-β) showed reactivation of HSV-1, with detectable plasma DNA. Finally, 1 cladribine-treated patient experienced VZV reactivation. All the reactivations of latent infections have been successfully treated., Conclusion: Screening of infectious diseases in DMT candidate MS patients helps to mitigate the infectious risk. During DMTs, a regular assessment of infectious risk allows to avoid discontinuing MS therapy and guarantees a higher degree of safety., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Introduction: Isolated head tremor, a pathological condition characterized by head tremor without dystonic postures or tremor in other body parts, has recently been suggested to be a form of dystonia. It is however still unclear whether isolated head tremor precedes dystonia or remains unmodified overtime., Methods: We enrolled 20 patients with isolated head tremor. For each patient, we assessed videos recorded at enrollment and after 5 years. The videotapes were reviewed by two independent experienced movement disorder specialists who evaluated and scored tremor and CD severity using the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor and the revised Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), respectively., Results: Upon enrollment, all 20 patients showed isolated head tremor. Mean tremor severity was 2.7 ± 0.9 as measured using the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor total score. At the 5-year follow-up examination, 15 (75%) of the 20 patients with isolated head tremor showed dystonic postures in the neck, while the remaining 5 patients (25%) had only isolated head tremor. Mean severity of dystonia as measured using the TWSTRS-2 total score was 11.8 ± 3.6. Head tremor severity was unchanged between baseline and the 5-year follow-up examination (p > 0.05). At the follow-up examination, no patients had tremor or dystonia in a body part other than the neck, nor did they develop bradykinesia or other parkinsonian signs., Conclusions: Our longitudinal study demonstrated that patients with isolated head tremor may develop cervical dystonia over time., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: The aim of this study was to investigate the relationship between suicidal ideation and neurological, psychological, and psychiatric features in patients with blepharospasm (BSP)., Methods: We enrolled 70 BSP patients and 80 control subjects. All participants underwent a psychiatric and psychometric evaluation: Structured Clinical Interview, Clinical Global Impression, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, Columbia-Suicide Severity Rating Scale, Beck Hopelessness Scale, Temperament Evaluation of Memphis, Pisa, San Diego Auto-questionnaire. BSP severity was assessed using the Blepharospasm Severity Rating Scale., Results: Suicidal ideation was reported in 18% of BSP patients and 6% had current suicidal ideation. 83% of BSP patients had severe hopelessness. BSP patients presented an increased sense of hopelessness (OR= 1.39, 95% CI = 1.13/1.70) and a pronounced depressive temperament (OR= 1.36, 95% CI = 1.12/1.65). Suicidal ideation in BSP patients correlated with psychiatric disorders (OR = 3.96, 95% CI = 1.23/12.74) and higher scores on the HAM-A (OR = 1.11, 95% CI = 1.02/1.20), HAM-D (OR = 1.18, 95% CI = 1.05/1.32), CGI (OR = 1.85, 95% CI = 1.18/2.90), TEMPS-A Cyclothymia (OR = 1.16, 95% CI = 1.02/1.31)., Conclusion: Our findings suggest the presence of suicidal ideation and severe hopelessness in BSP patients.KEY POINTSBSP patients as compared to controls more frequently reported the presence of a psychiatric disorder and more severe anxiety and depressive symptoms, psychopathology on the CGI, suicidal ideation, and hopelessness.BSP patients with prevalent cyclothymic temperament had more severe suicidal ideation, suggesting an increased suicide risk most likely due to difficulties in psychological adaptation to changing environments, including the neurological disease.A psychiatric assessment is recommended for patients with this condition, with possible referral to a suicide prevention centre.

Background: Frailty is an age-related status of increased vulnerability to stressors caused by the accumulation of multiple health deficits. This construct may allow to capture the clinical complexity of patients with multiple sclerosis (MS)., Objective: To investigate the relationship between frailty and the clinical manifestations of MS., Methods: Patients with MS were consecutively enrolled at five tertiary dedicated services. Disability and fatigue were assessed. The phenotypes of MS were also identified. Frailty was measured using a frailty index (FI), computed by cumulatively considering 42 age-related multidimensional health deficits., Results: Overall, 745 MS patients (mean age = 48.2 years, standard deviation = 11.7 years; women 68%) were considered. The median FI value was 0.12 (interquartile range = 0.05-0.19) and the 99th percentile was 0.40. FI scores were associated with MS disease duration, disability, fatigue, as well as with the number of previous disease-modifying treatments and current symptomatic therapies. A logistic regression analysis model showed that FI score was independently associated with the secondary progressive phenotype., Conclusion: Frailty is significantly associated with major characteristics of MS. The findings of the present cross-sectional investigation should be explored in future longitudinal studies.

Background and Aims: Most patients with multiple sclerosis presenting with a relapsing-remitting disease course at diagnosis transition to secondary progressive multiple sclerosis (SPMS) 1-2 decades after onset. SPMS is characterized by predominant neurodegeneration and atrophy. These pathogenic hallmarks result in unsatisfactory treatment response in SPMS patients. Therefore, early diagnosis of SPMS is necessary for prompt treatment decisions. The aim of this review was to assess neurophysiological and fluid biomarkers that have the potential to monitor disease progression and support early SPMS diagnosis., Methods: We performed a systematic review of studies that analyzed the role of neurophysiological techniques and fluid biomarkers in supporting SPMS diagnosis using the preferred reporting items for systematic reviews and meta-analyses statement., Results: From our initial search, we selected 24 relevant articles on neurophysiological biomarkers and 55 articles on fluid biomarkers., Conclusion: To date, no neurophysiological or fluid biomarker is sufficiently validated to support the early diagnosis of SPMS. Neurophysiological measurements, including short interval intracortical inhibition and somatosensory temporal discrimination threshold, and the neurofilament light chain fluid biomarker seem to be the most promising. Cross-sectional studies on an adequate number of patients followed by longitudinal studies are needed to confirm the diagnostic and prognostic value of these biomarkers. A combination of neurophysiological and fluid biomarkers may be more sensitive in detecting SPMS conversion., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Patients with cervical dystonia (CD) may display non-motor symptoms, including psychiatric disturbances, pain, and sleep disorders. Intramuscular injection of botulinum toxin type A (BoNT-A) is the most efficacious treatment for motor symptoms in CD, but little is known about its effects on non-motor manifestations. The aim of the present study was to longitudinally assess BoNT-A's effects on CD non-motor symptoms and to investigate the relationship between BoNT-A-induced motor and non-motor changes. Forty-five patients with CD participated in the study. Patients underwent a clinical assessment that included the administration of standardized clinical scales assessing dystonic symptoms, psychiatric disturbances, pain, sleep disturbances, and disability. Clinical assessment was performed before and one and three months after BoNT-A injection. BoNT-A induced a significant improvement in dystonic symptoms, as well as in psychiatric disturbances, pain, and disability. Conversely, sleep disorders were unaffected by BoNT-A treatment. Motor and non-motor BoNT-A-induced changes showed a similar time course, but motor improvement did not correlate with non-motor changes after BoNT-A. Non-motor symptom changes after BoNT-A treatment are a complex phenomenon and are at least partially independent from motor symptom improvement.

Introduction: Physical fatigue can be a common reason for early retirement or sick leave since it appears in the earliest stages of multiple sclerosis (MS). Therefore, a prompt and accurate diagnosis is essential. This systematic review aims to identify and describe the instruments used to assess physical fatigue in MS patients with consideration for the languages used to validate the instruments and their methodological qualities., Area Covered: This study has been carried out through 'Medline,' 'Scopus,' 'Cinhal,' and 'Web of Science' databases for all the papers published before 24 January 2020. Three independent authors have chosen the eligible studies based upon pre-set criteria of inclusion. Data collection, data items, and assessment of the risk of bias: the data extraction approach was chosen based on the Cochrane Methods. For data collection, the authors followed the recommendations from the COSMIN initiative. Study quality and risk of bias were assessed using the COSMIN Check List., Expert Opinion: 119 publications have been reviewed. The 45 assessment scales can be divided into specific scales for physical fatigue and specific scales for MS. The most popular tools are the Fatigue Severity Scale and the Modified Fatigue Impact Scale.

Background: Patients with cervical dystonia (CD) show impaired postural control, balance, and gait, likely due to abnormal head postures and sensorimotor disturbances. However, until now no study has investigated whether attention-demanding activity worsens postural control and balance in CD patients. Objective: To investigate whether patients with CD show cognitive-motor interference (CMI), a specific kind of dual-task interference that occurs during the simultaneous execution of a cognitive and motor task. This information may be useful to determine whether performing activities of daily living worsens postural control and balance in CD patients. Methods: We performed a pilot case-control study. Twenty-two patients affected by CD and 19 healthy controls were enrolled in order to test CMI. Each subject was evaluated during the execution of a cognitive task while postural stability was assessed through a stabilometric platform. Results: CD patients showed impaired postural control compared to healthy controls, with instability increasing with increasing cognitive task complexity. No relationships were found between stabilometric parameters and clinical characteristics of CD. Conclusions: Our hypothesis is that CMI in CD patients derives from deranged network connectivity when activated simultaneously during the performance of two tasks that interfere with each other and "compete" for the same resources within the cognitive system., 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 Baione, Ferrazzano, Celletti, De Rosa, Belvisi, Fabbrini, Galli, Camerota and Conte.)

Introduction: Individuals with Guillain-Barrè syndrome (GBS) showed significant longer-term psychological sequelae, due to persistent disability. In recent years, great advances have been made in medical care for patients with GBS. However, the focus has been mainly on patient care in the acute phase and improving survival instead of long-term disability. The purpose of this study was to evaluate the efficacy of rehabilitation in people with GBS through a systematic review of randomized controlled trials., Area Covered: PRISMA guidelines were used to perform this systematic review. Six bibliographic databases were searched: PUBMED, WEB OF SCIENCE, PEDro, CINHAL, PSYCHINFO, and SCOPUS. Papers included in the systematic review should have a search design of a randomized controlled trial. The quality of the clinical trials included was evaluated according to Jadad score., Expert Opinion: After eliminating duplicates, 472 records got screened, three RCTs were included in the systematic review. Overall, the analysis of the three randomized controlled trials showed that various types of rehabilitation interventions are correlated to an improvement in the patient's well-being. Finally, it is not possible to extrapolate definite conclusions on the effectiveness of rehabilitation treatment in patients with GBS. Therefore, high-quality future studies are needed to confirm these hypotheses.

(1) Background: In dystonia, the somatosensory temporal discrimination threshold (STDT) is abnormally increased at rest and higher and longer-lasting during movement execution in comparison with healthy subjects (HS), suggesting an abnormal sensorimotor integration. These abnormalities are thought to depend on abnormal proprioceptive input coming from dystonic muscles. Since Botulinum toxin-A (BT-A) reduces proprioceptive input in the injected muscles, our study investigated the effects of BT-A on STDT tested at rest and during voluntary movement execution in patients with focal dystonia. (2) Methods: We enrolled 35 patients with focal dystonia: 14 patients with cervical dystonia (CD), 11 patients with blepharospasm (BSP), and 10 patients with focal hand dystonia (FHD); and 12 age-matched HS. STDT tested by delivering paired stimuli was measured in all subjects at rest and during index finger abductions. (3) Results: Patients with dystonia had higher STDT values at rest and during movement execution than HS. While BT-A did not modify STDT at rest, it reduced the abnormal values of STDT during movement in CD and FHD patients, but not in BSP patients. (4) Conclusions: BT-A improved abnormal sensorimotor integration in CD and FHD, most likely by decreasing the overflow of proprioceptive signaling from muscle dystonic activity to the thalamus.

Background: Previous studies on patients with Multiple Sclerosis (MS) have reported contrasting findings on cortical plasticity of the primary motor cortex and no study has yet evaluated the regulatory mechanisms of cortical plasticity (i.e., metaplasticity) in MS patients. The aim of the present study was to investigate primary motor cortex (M1) plasticity and metaplasticity in patients with MS., Methods: Nineteen patients affected by Relapsing--Remitting MS (RR-MS) and 16 age- and sex-matched healthy controls underwent intermittent Theta Burst Stimulation (iTBS) to evaluate cortical plasticity and iTBS preceded by repetitive index finger movements to evaluate M1 metaplasticity., Results: In healthy subjects MEP size significantly increased after iTBS whereas it significantly decreased when repetitive index finger movements preceded iTBS (metaplasticity) (factor PROTOCOL: p < 0.0001; PROTOCOL x TIME interaction: p = 0.001). Conversely, in MS patients MEP size mildly increased, albeit not significantly in both conditions (p > 0.05). In MS patients, percentage changes in MEP size induced by plasticity and metaplasticity protocol were significantly associated to EDSS (p = 0.001) and kinematics of index finger movements (p = 0.01)., Conclusion: M1 plasticity and metaplasticity are both altered in MS patients. When TBS is used for therapeutic purposes, TBS protocols should be tailored according to the M1 plasticity functional reserve of each MS patient., Competing Interests: Declaration of Competing Interest No competing interests to declare., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Patients with blepharospasm in addition to involuntary contraction of the orbicularis oculi muscle also have non-motor symptoms (psychiatric, sleep, cognitive, and ocular). In this paper, we investigated the relationship of non-motor with motor symptoms and the total burden of non-motor symptoms in patients with blepharospasm. Results were compared with those of age- and sex-matched healthy controls., Methods: We enrolled 60 patients with blepharospasm and 40 age-matched healthy controls. In all patients, the severity of blepharospasm was assessed clinically with the Blepharospasm Severity Rating Scale. All the participants underwent a psychiatric, sleep, cognitive, and ocular symptom evaluation. We investigated the correlations between motor, non-motor symptoms, and patients' clinical and demographic features., Results: The frequency of psychiatric, sleep, and cognitive disorders and ocular symptoms was higher in blepharospasm patients than in healthy controls. Non-motor symptoms coexisted in the majority of patients and there was no correlation between non-motor and motor symptoms. The total burden of non-motor symptoms did not associate with motor symptoms and demographic features in blepharospasm., Conclusions: Non-motor symptoms are independent of motor features and likely belong to the clinical spectrum of blepharospasm. The presence of non-motor symptoms possibly reflects a complex network disorder of blepharospasm.

The aim of the study was to evaluate the effects of writing, reading, and speaking on orbiculari oculi (OO) muscle spasms and on the blink rate in patients with blepharospasm (BSP). Patients with hemifacial spasm (HFS) and healthy subjects (HS) acted as control subjects. Thirty patients with BSP, 20 patients with primary HFS and 20 age-matched healthy subjects were videotaped according to a standardized procedure: at rest with eyes open; while writing a standard sentence on paper; while writing a standard sentence on a blackboard keeping the head straight; during a conversation based on a simple topic (speaking task); and while reading a standard text aloud. Two independent movement disorders specialists reviewed the videotapes and measured the number of OO spasms and blinks in each segment. Writing and reading reduced the number of OO spasms in BSP patients, whereas speaking did not. On the other hand, writing, reading, and speaking did not modify spasms in HFS patients. These tasks modulated the blink rate in all the three groups of subjects (BSP, HFS, and HS). Our hypothesis is that the modulation of OO spasm in BSP during writing and reading depends on influences coming from occipital areas onto the brainstem circuits. Whether cognitive training with reading and writing may be used to improve OO muscle spasms is an issue that warrants further investigation.

Evidence shows altered somatosensory temporal discrimination threshold (STDT) in Parkinson's disease in comparison to normal subjects. In healthy subjects, movement execution modulates STDT values through mechanisms of sensory gating. We investigated whether STDT modulation during movement execution in patients with Parkinson's disease differs from that in healthy subjects. In 24 patients with Parkinson's disease and 20 healthy subjects, we tested STDT at baseline and during index finger abductions (at movement onset "0", 100, and 200 ms thereafter). We also recorded kinematic features of index finger abductions. Fifteen out of the 24 patients were also tested ON medication. In healthy subjects, STDT increased significantly at 0, 100, and 200 ms after movement onset, whereas in patients with Parkinson's disease in OFF therapy, it increased significantly at 0 and 100 ms but returned to baseline values at 200 ms. When patients were tested ON therapy, STDT during index finger abductions increased significantly, with a time course similar to that of healthy subjects. Differently from healthy subjects, in patients with Parkinson's disease, the mean velocity of the finger abductions decreased according to the time lapse between movement onset and the delivery of the paired electrical stimuli for testing somatosensory temporal discrimination. In conclusion, patients with Parkinson's disease show abnormalities in the temporal coupling between tactile information and motor outflow. Our study provides first evidence that altered temporal processing of sensory information play a role in the pathophysiology of motor symptoms in Parkinson's disease.

Background: In multiple sclerosis (MS), pathophysiology of fatigue is only partially known., Objective: The aim of this study was to investigate whether the attention-induced modulation on short- and long-term cortical plasticity mechanisms in primary motor area (M1) is abnormal in patients with MS-related fatigue., Methods: All participants underwent 5-Hz repetitive transcranial magnetic stimulation (rTMS), reflecting short-term plasticity, and paired associative stimulation (PAS), reflecting long-term plasticity, and were asked to focus their attention on the hand contralateral to the M1 stimulated. A group of age-matched healthy subjects acted as control., Results: In patients with MS, 5-Hz rTMS and PAS failed to induce the normal increase in motor-evoked potential (MEP). During the attention-demanding condition, 5-Hz rTMS- and PAS-induced responses differed in patients with MS with and without fatigue. Whereas in patients with fatigue neither technique induced the attention-induced MEP increase, in patients without fatigue they both increased the MEP response, although they did so less efficiently than in healthy subjects. Attention-induced changes in short-term cortical plasticity inversely correlated with fatigue severity., Conclusion: Short-term and long-term plasticity mechanisms are abnormal in MS possibly owing to widespread changes in ion-channel expression. Fatigue in MS reflects disrupted cortical attentional networks related to movement control., (© The Author(s), 2015.)