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Daniele Belvisi,1 Isabella Berardelli,2 Antonio Suppa,1,3 Andrea Fabbrini,3 Massimo Pasquini,3 Maurizio Pompili,2 Giovanni Fabbrini1,3 1IRCCS Neuromed, Pozzilli, Italy; 2Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention Center, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy; 3Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy Abstract: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) are the most common atypical parkinsonisms. These disorders are characterized by varying combinations of autonomic, cerebellar and pyramidal system, and cognitive dysfunctions. In this paper, we reviewed the evidence available on the presence and type of neuropsychiatric disturbances in MSA, PSP, and CBD. A MedLine, Excerpta Medica, PsycLit, PsycInfo, and Index Medicus search was performed to identify all articles published on this topic between 1965 and 2018. Neuropsychiatric disturbances including depression, anxiety, agitation, and behavioral abnormalities have been frequently described in these disorders, with depression as the most frequent disturbance. MSA patients show a higher frequency of depressive disorders when compared to healthy controls. An increased frequency of anxiety disorders has also been reported in some patients, and no studies have investigated apathy. PSP patients may have depression, apathy, disinhibition, and to a lesser extent, anxiety and agitation. In CBD, neuropsychiatric disorders are similar to those present in PSP. Hallucinations and delusions are rarely reported in these disorders. Neuropsychiatric symptoms in MSA, PSP, and CBD do not appear to be related to the severity of motor dysfunction and are one of the main factors that determine a low quality of life. The results suggest that neuropsychiatric disturbances should always be assessed in patients with atypical parkinsonisms. Keywords: atypical parkinsonisms, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, neuropsychiatric disturbances, depression

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.

Alzheimer disease (AD) remains a significant global health concern. The progression from preclinical stages to overt dementia has become a crucial point of interest for researchers. This paper reviews the potential of neurophysiological biomarkers in predicting AD progression, based on a systematic literature search following PRISMA guidelines, including 55 studies. EEG-based techniques have been predominantly employed, whereas TMS studies are less common. Among the investigated neurophysiological measures, spectral power measurements and event-related potentials-based measures, including P300 and N200 latencies, have emerged as the most consistent and reliable biomarkers for predicting the likelihood of conversion to AD. In addition, TMS-based indices of cortical excitability and synaptic plasticity have also shown potential in assessing the risk of conversion to AD. However, concerns persist regarding the methodological discrepancies among studies, the accuracy of these neurophysiological measures in comparison to established AD biomarkers, and their immediate clinical applicability. Further research is needed to validate the predictive capabilities of EEG and TMS measures. Advancements in this area could lead to cost-effective, reliable biomarkers, enhancing diagnostic processes and deepening our understanding of AD pathophysiology., (© 2024. The Author(s).)

The search for reliable and easily accessible biomarkers in Parkinson's disease is receiving a growing emphasis, to detect neurodegeneration from the prodromal phase and to enforce disease-modifying therapies. Despite the need for non-invasively accessible biomarkers, the majority of the studies have pointed to cerebrospinal fluid or peripheral biopsies biomarkers, which require invasive collection procedures. Saliva represents an easily accessible biofluid and an incredibly wide source of molecular biomarkers. In the present study, after presenting the morphological and biological bases for looking at saliva in the search of biomarkers for Parkinson's disease, we systematically reviewed the results achieved so far in the saliva of different cohorts of Parkinson's disease patients. A comprehensive literature search on PubMed and SCOPUS led to the discovery of 289 articles. After screening and exclusion, 34 relevant articles were derived for systematic review. Alpha-synuclein, the histopathological hallmark of Parkinson's disease, has been the most investigated Parkinson's disease biomarker in saliva, with oligomeric alpha-synuclein consistently found increased in Parkinson's disease patients in comparison to healthy controls, while conflicting results have been reported regarding the levels of total alpha-synuclein and phosphorylated alpha-synuclein, and few studies described an increased oligomeric alpha-synuclein/total alpha-synuclein ratio in Parkinson's disease. Beyond alpha-synuclein, other biomarkers targeting different molecular pathways have been explored in the saliva of Parkinson's disease patients: total tau, phosphorylated tau, amyloid-β1-42 (pathological protein aggregation biomarkers); DJ-1, heme-oxygenase-1, metabolites (altered energy homeostasis biomarkers); MAPLC-3beta (aberrant proteostasis biomarker); cortisol, tumor necrosis factor-alpha (inflammation biomarkers); DNA methylation, miRNA (DNA/RNA defects biomarkers); acetylcholinesterase activity (synaptic and neuronal network dysfunction biomarkers); Raman spectra, proteome, and caffeine. Despite a few studies investigating biomarkers targeting molecular pathways different from alpha-synuclein in Parkinson's disease, these results should be replicated and observed in studies on larger cohorts, considering the potential role of these biomarkers in determining the molecular variance among Parkinson's disease subtypes. Although the need for standardization in sample collection and processing, salivary-based biomarkers studies have reported encouraging results, calling for large-scale longitudinal studies and multicentric assessments, given the great molecular potentials and the non-invasive accessibility of saliva., (Copyright © 2024 Copyright: © 2024 Neural Regeneration Research.)

Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence ('wearing-off') before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab's effect on MS-related fatigue. Forty-five relapsing-remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off., (© 2024. The Author(s).)

Background: Assessment of upper limb function is critical in the rehabilitation process of people with Parkinson's Disease (PD), and universally validated outcome measures are needed to allow comparisons across the practice. Moreover, the study of psychometric properties of the same tool on different clinical populations guarantees the possibility of reliably evaluating the same rehabilitation treatment in people with different clinical conditions., Aim of the Study: The aim of this research was to evaluate the psychometric characteristics of the Italian adaptation of the Jebsen Taylor Hand Function Test (JTHFT) in individuals with PD., Methods: The reliability and validity of the test were assessed in accordance with international standards. Internal consistency was measured using Cronbach's alpha, and test-retest reliability was determined via the intraclass correlation coefficient (ICC). The construct validity and cross-cultural validity of the test were evaluated using Pearson's correlation coefficient with three assessment tools on upper limb function, independence, and quality of life, with hand grip power measured by a dynamometer and an Italian pangram. Finally, responsiveness after a one month of rehabilitation treatment was measured using the Wilcoxon rank test., Results: Fifty-two Italian people with PD were recruited. Cronbach's alpha values ranged from 0.556 (non-dominant hand) to 0.668 (dominant hand); ICC values ranged from 0.754 to 0.988. Construct validity showed that several statistically significant correlations were detected. Wilcoxon's test showed that the assessment tool can detect a change in this population after treatment., Conclusions: The JTHFT is a reliable, valid, and respondent tool to evaluate the upper limb and hand functionalities in PD patients. It should be added to the toolkit for measuring upper limb performance in this population, adding value to clinical evaluation and ensuring comparable results for different clinical populations and different countries.

The current hypothesis on the pathophysiology of multiple sclerosis (MS) suggests the involvement of both inflammatory and neurodegenerative mechanisms. Disease Modifying Therapies (DMTs) effectively decrease relapse rates, thus reducing relapse-associated disability in people with MS. In some patients, disability progression, however, is not solely linked to new lesions and clinical relapses but can manifest independently. Progression Independent of Relapse Activity (PIRA) significantly contributes to long-term disability, stressing the urge to unveil biomarkers to forecast disease progression. Twenty-five adult patients with relapsing-remitting multiple sclerosis (RRMS) were enrolled in a cohort study, according to the latest McDonald criteria, and tested before and after high-efficacy Disease Modifying Therapies (DMTs) (6-24 months). Through Agilent microarrays, we analyzed miRNA profiles from peripheral blood mononuclear cells. Multivariate logistic and linear models with interactions were generated. Robustness was assessed by randomization tests in R. A subset of miRNAs, correlated with PIRA, and the Expanded Disability Status Scale (EDSS), was selected. To refine the patient stratification connected to the disease trajectory, we computed a robust logistic classification model derived from baseline miRNA expression to predict PIRA status (AUC = 0.971). We built an optimal multilinear model by selecting four other miRNA predictors to describe EDSS changes compared to baseline. Multivariate modeling offers a promising avenue to uncover potential biomarkers essential for accurate prediction of disability progression in early MS stages. These models can provide valuable insights into developing personalized and effective treatment strategies.

Oligomeric alpha-synuclein (α-syn) in saliva and phosphorylated α-syn deposits in the skin have emerged as promising diagnostic biomarkers for Parkinson's disease (PD). This study aimed to assess and compare the diagnostic value of these biomarkers in discriminating between 38 PD patients and 24 healthy subjects (HSs) using easily accessible biological samples. Additionally, the study sought to determine the diagnostic potential of combining these biomarkers and to explore their correlations with clinical features. Salivary oligomeric α-syn levels were quantified using competitive ELISA, while skin biopsies were analyzed through immunofluorescence to detect phosphorylated α-syn at Ser129 (p-S129). Both biomarkers individually were accurate in discriminating PD patients from HSs, with a modest agreement between them. The combined positivity of salivary α-syn oligomers and skin p-S129 aggregates differentiated PD patients from HSs with an excellent discriminative ability with an AUC of 0.9095. The modest agreement observed between salivary and skin biomarkers individually suggests that they may reflect different aspects of PD pathology, thus providing complementary information when combined. This study's results highlight the potential of utilizing a multimodal biomarker approach to enhance diagnostic accuracy in PD.

Background: Aging clocks tag the actual underlying age of an organism and its discrepancy with chronological age and have been reported to predict incident disease risk in the general population. However, the relationship with neurodegenerative risk and in particular with Parkinson's Disease (PD) remains unclear, with few discordant findings reporting associations with both incident and prevalent PD risk., Objective: To clarify this relationship, we computed a common aging clock based on blood markers and tested the resulting discrepancy with chronological age (ΔPhenoAge) for association with both incident and prevalent PD risk., Methods: In a large Italian population cohort - the Moli-sani study (N=23,437; age ≥ 35 years; 52% women) - we carried out both Cox Proportional Hazards regressions modelling ΔPhenoAge as exposure and incident PD as outcome, and linear models testing prevalent PD as exposure and ΔPhenoAge as outcome. All models were incrementally adjusted for age, sex, education level completed and other risk/protective factors previously associated with PD risk in the same cohort (prevalent dysthyroidism, hypertension, diabetes, use of oral contraceptives, exposure to paints, daily coffee intake and cigarette smoking)., Results: No significant association between incident PD risk (209 cases, median (IQR) follow-up time 11.19 (2.03) years) and PhenoAging was observed (Hazard Ratio [95% Confidence Interval] = 0.98 [0.71; 1.37]). However, a small but significant increase of ΔPhenoAge was observed in prevalent PD cases vs healthy subjects (β (Standard Error) = 1.39 (0.70)). An analysis of each component biomarker of PhenoAge revealed a significant positive association of prevalent PD status with red cell distribution width (RDW; β (SE) = 0.46 (0.18)). All the remaining markers did not show any significant evidence of association., Conclusion: The reported evidence highlights systemic effects of prevalent PD status on biological aging and red cell distribution width. Further cohort and functional studies may help shedding a light on the related pathways altered at the organism level in prevalent PD, like red cells variability, inflammatory and oxidative stress 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gialluisi, Tirozzi, Costanzo, De Bartolo, Belvisi, Magnacca, De Curtis, Falciglia, Ricci, Cerletti, Donati, Berardelli, de Gaetano and Iacoviello.)

Background: Ischemic stroke may trigger neuroplastic changes via proliferation, migration towards the lesion, and differentiation of neuroprogenitor cells into mature neurons. Repetitive Transcranial Magnetic Stimulation (rTMS) may promote brain plasticity. This study aimed to assess rTMS's effect on post-stroke endogenous neuroplasticity by dosing plasma miRs 17~92, Netrin-1, Sema3A, and BDNF., Methods: In this case-controlled study, we randomized 19 ischemic stroke patients within five days from symptoms onset (T0) to neuronavigated-rTMS or sham stimulation. Stimulation was applied on the stroke hemisphere daily between the 7th and 14th day from stroke onset. Blood samples were collected at T0, before the first rTMS section (T7), and at the end of the last rTMS session (T14). Five healthy controls were also enrolled in this study., Results: Of 19 patients, 10 received rTMS and 9 sham stimulation. Compared with the sham group, in the rTMS group, plasma levels of miRs17~92 and Ntn-1 significantly increased whereas Sema3A levels tended to decrease. In multivariate linear regression analyses, rTMS was independently related to Ntn-1 and miR-25 levels at T14., Conclusions: We found an association between rTMS and neurogenesis/axonogenesis biomarker enhancement. Our preliminary data suggest that rTMS may positively interfere with natural endogenous plasticity phenomena of the post-ischemic human brain.

Botulinum toxin (BoNT) is an effective and safe therapy for the symptomatic treatment of several neurological disturbances. An important line of research has provided numerous pieces of evidence about the mechanisms of action of BoNT in the central nervous system, especially in the context of dystonia and spasticity. However, only a few studies focused on the possible central effects of BoNT in Parkinson's disease (PD). We performed a systematic review to describe and discuss the evidence from studies focused on possible central effects of BoNT in PD animal models and PD patients. To this aim, a literature search in PubMed and SCOPUS was performed in May 2023. The records were screened according to title and abstract by two independent reviewers and relevant articles were selected for full-text review. Most of the papers highlighted by our review report that the intrastriatal administration of BoNT, through local anticholinergic action and the remodulation of striatal compensatory mechanisms secondary to dopaminergic denervation, induces an improvement in motor and non-motor symptoms in the absence of neuronal loss in animal models of PD. In human subjects, the data are scarce: a single neurophysiological study in tremulous PD patients found that the change in tremor severity after peripheral BoNT administration was associated with improved sensory-motor integration and intracortical inhibition measures. Further clinical, neurophysiological, and neuroimaging studies are necessary to clarify the possible central effects of BoNT in PD.

Background and Objectives: Multiple sclerosis (MS) is a chronic, progressive neurological disease characterized by early-stage neuroinflammation, neurodegeneration, and demyelination that involves a spectrum of heterogeneous clinical manifestations in terms of disease course and response to therapy. Even though several disease-modifying therapies (DMTs) are available to prevent MS-related brain damage-acting on the peripheral immune system with an indirect effect on MS lesions-individualizing therapy according to disease characteristics and prognostic factors is still an unmet need. Given that deregulated miRNAs have been proposed as diagnostic tools in neurodegenerative/neuroinflammatory diseases such as MS, we aimed to explore miRNA profiles as potential classifiers of the relapsing-remitting MS (RRMS) patients' prospects to gain a more effective DMT choice and achieve a preferential drug response., Methods: A total of 25 adult patients with RRMS were enrolled in a cohort study, according to the latest McDonald criteria before (pre-cladribine, pre-CLA; pre-ocrelizumab, pre-OCRE, time T0) and after high-efficacy DMTs, time T1, 6 months post-CLA ( n = 10, 7 F and 3 M, age 39.0 ± 7.5) or post-OCRE ( n = 15, 10 F and 5 M, age 40.5 ± 10.4) treatment. A total of 15 age- and sex-matched healthy control subjects (9 F and 6 M, age 36.3 ± 3.0) were also selected. By using Agilent microarrays, we analyzed miRNA profiles from peripheral blood mononuclear cells (PBMC). miRNA-target networks were obtained by miRTargetLink, and Pearson's correlation served to estimate the association between miRNAs and outcome clinical features., Results: First, the miRNA profiles of pre-CLA or pre-OCRE RRMS patients compared to healthy controls identified modulated miRNA patterns (40 and seven miRNAs, respectively). A direct comparison of the two pre-treatment groups at T0 and T1 revealed more pro-inflammatory patterns in the pre-CLA miRNA profiles. Moreover, both DMTs emerged as being capable of reverting some dysregulated miRNAs toward a protective phenotype. Both drug-dependent miRNA profiles and specific miRNAs, such as miR-199a-3p, miR-29b-3p, and miR-151a-3p, emerged as potentially involved in these drug-induced mechanisms. This enabled the selection of miRNAs correlated to clinical features and the related miRNA-mRNA network., Discussion: These data support the hypothesis of specific deregulated miRNAs as putative biomarkers in RRMS patients' stratification and DMT drug response., Competing Interests: SC received travel grants from Merck and Novartis. ACo received consulting research funding from Novartis, Roche, Biogen, Merck Serono, and Almirall. MS received research support and has received fees as speaker from Sanofi, Biogen, Roche, Novartis, Bayer Schering, and Merck Serono. 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., (Copyright © 2023 Arisi, Malimpensa, Manzini, Brandi, Gosetti di Sturmeck, D’Amelio, Crisafulli, Ferrazzano, Belvisi, Malerba, Florio, Pascale, Soreq, Salvetti, Cattaneo, D’Onofrio and Conte.)

Postural instability (PI) in Parkinson's disease (PD) exposes patients to an increased risk of falls (RF). While dopaminergic therapy and deep brain stimulation (DBS) improve motor performance in advanced PD patients, their effects on PI and RF remain elusive. PI and RF were assessed using a stabilometric platform in six advanced PD patients. Patients were evaluated in OFF and ON dopaminergic medication and under four DBS settings: with DBS off, DBS bilateral, and unilateral DBS of the more- or less-affected side. Our findings indicate that dopaminergic medication by itself exacerbated PI and RF, and DBS alone led to a decline in RF. No combination of medication and DBS yielded a superior improvement in postural control compared to the baseline combination of OFF medication and the DBS-off condition. Yet, for ON medication, DBS significantly improved both PI and RF. Among DBS conditions, DBS bilateral provided the most favorable outcomes, improving PI and RF in the ON medication state and presenting the smallest setbacks in the OFF state. Conversely, the more-affected side DBS was less beneficial. These preliminary results could inform therapeutic strategies for advanced PD patients experiencing postural disorders.

Background: Distal upper limb tremor during walking (TW) is frequently observed in Parkinson's disease (PD) but its clinical features are unknown., Objective: To characterize the occurrence and the clinical features of TW in comparison to the other types of tremors in PD., Methods: Fifty-one PD patients with rest tremor were evaluated off- and on-treatment. Occurrence, body distribution, severity and latency of TW and of other tremor types were assessed., Results: TW was present in 78% of the PD patients examined. TW body distribution and severity were similar to those of rest and re-emergent tremor but different from the postural tremor presented by the same patients. TW latency, observed in 85% of patients, was on average 5.8 s. Dopaminergic treatment significantly improved TW, rest, and re-emergent tremor severity but left TW latency unaffected., Conclusions: TW is a frequent motor sign in PD and is likely a clinical variant of rest tremor., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Paired associative stimulation (PAS) is a non-invasive brain stimulation technique that modulates synaptic plasticity in the human motor cortex (M1). Since previous studies have primarily used motor-evoked potentials (MEPs) as outcome measure, cortical correlates of PAS-induced plasticity remain unknown. Therefore, the aim of this observational study was to investigate cortical correlates of a standard PAS induced plasticity in the primary motor cortex by using a combined TMS-EEG approach in a cohort of eighteen healthy subjects. In addition to the expected long-lasting facilitatory modulation of MEPs amplitude, PAS intervention also induced a significant increase in transcranial magnetic stimulation-evoked potentials (TEPs) P30 and P60 amplitude. No significant correlation between the magnitude of PAS-induced changes in TEP components and MEP amplitude were observed. However, the linear regression analysis revealed that the combined changes in P30 and P60 component amplitudes significantly predicted the MEP facilitation after PAS. The findings of our study offer novel insight into the neurophysiological changes associated with PAS-induced plasticity at M1 cortical level and suggest a complex relationship between TEPs and MEPs changes following PAS.

Background: To date, a few studies have systematically investigated differences in the clinical spectrum between acquired and idiopathic dystonias., Objectives: To compare demographic data and clinical features in patients with adult-onset acquired and idiopathic dystonias., Methods: Patients were identified from among those included in the Italian Dystonia Registry, a multicenter Italian dataset of patients with adult-onset dystonia. Study population included 116 patients with adult-onset acquired dystonia and 651 patients with isolated adult-onset idiopathic dystonia., Results: Comparison of acquired and idiopathic dystonia revealed differences in the body distribution of dystonia, with oromandibular dystonia, limb and trunk dystonia being more frequent in patients with acquired dystonia. The acquired dystonia group was also characterized by lower age at dystonia onset, greater tendency to spread, lower frequency of head tremor, sensory trick and eye symptoms, and similar frequency of neck pain associated with CD and family history of dystonia/tremor., Conclusions: The clinical phenomenology of dystonia may differ between acquired and idiopathic dystonia, particularly with regard to the body localization of dystonia and the tendency to spread. This dissimilarity raises the possibility of pathophysiological differences between etiologic categories., (© 2023 International Parkinson and Movement Disorder Society.)

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.)

Background : The ability to perceive two tactile stimuli as asynchronous can be measured using the somatosensory temporal discrimination threshold (STDT). In healthy humans, the execution of a voluntary movement determines an increase in STDT values, while the integration of STDT and movement execution is abnormal in patients with basal ganglia disorders. Sensorimotor integration can be modulated using focal muscle vibration (fMV), a neurophysiological approach that selectively activates proprioceptive afferents from the vibrated muscle. Method : In this study, we investigated whether fMV was able to modulate STDT or STDT-movement integration in healthy subjects by measuring them before, during and after fMV applied over the first dorsalis interosseous, abductor pollicis brevis and flexor radialis carpi muscles. Results : The results showed that fMV modulated STDT-movement integration only when applied over the first dorsalis interosseous, namely, the muscle performing the motor task involved in STDT-movement integration. These changes occurred during and up to 10 min after fMV. Differently, fMV did not influence STDT at rest. We suggest that that fMV interferes with the STDT-movement task processing, possibly disrupting the physiological processing of sensory information. Conclusions : This study showed that FMV is able to modulate STDT-movement integration when applied over the muscle involved in the motor task. This result provides further information on the mechanisms underlying fMV, and has potential future implications in basal ganglia disorders characterized by altered sensorimotor integration.

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.)

Dystonia is thought to be a network disorder due to abnormalities in the basal ganglia-thalamo-cortical circuit. We aimed to investigate the white matter (WM) microstructural damage of bundles connecting pre-defined subcortical and cortical regions in cervical dystonia (CD) and blepharospasm (BSP). Thirty-five patients (17 with CD and 18 with BSP) and 17 healthy subjects underwent MRI, including diffusion tensor imaging (DTI). Probabilistic tractography (BedpostX) was performed to reconstruct WM tracts connecting the globus pallidus, putamen and thalamus with the primary motor, primary sensory and supplementary motor cortices. WM tract integrity was evaluated by deriving their DTI metrics. Significant differences in mean, radial and axial diffusivity between CD and HS and between BSP and HS were found in the majority of the reconstructed WM tracts, while no differences were found between the two groups of patients. The observation of abnormalities in DTI metrics of specific WM tracts suggests a diffuse and extensive loss of WM integrity as a common feature of CD and BSP, aligning with the increasing evidence of microstructural damage of several brain regions belonging to specific circuits, such as the basal ganglia-thalamo-cortical circuit, which likely reflects a common pathophysiological mechanism of focal dystonia.

Patients with cervical dystonia (CD) often show an improvement in dystonic posture after sensory trick (ST), though the mechanisms underlying ST remain unclear. In this study, we aimed to investigate the effects of ST on cortical activity in patients with CD and to explore the contribution of motor and sensory components to ST mechanisms. To this purpose, we studied 15 CD patients with clinically effective ST, 17 without ST, and 14 healthy controls (HCs) who mimicked the ST. We used electroencephalographic (EEG) recordings and electromyography (EMG) data from bilateral sternocleidomastoid (SCM) muscles. We compared ST-related EEG spectral changes from sensorimotor and posterior parietal areas and EMG power changes between groups. To better understand the contribution of motor and sensory components to ST, we tested EEG and EMG correlates of three different conditions mimicking ST, the first without skin touch ("no touch" condition), the second without voluntary movements ("passive" condition), and finally without arm movements ("examiner touch" condition). Results showed ST-related alpha desynchronization in the sensorimotor cortex and theta desynchronization in the sensorimotor and posterior parietal cortex. Both spectral changes were more significant during maneuver execution in CD patients with ST than in CD patients without ST and HCs who mimicked the ST. Differently, the "no touch", "passive", or "examiner touch" conditions did not show significant differences in EEG or EMG changes determined by ST execution/mimicking between CD patients with or without ST. A higher desynchronization within alpha and theta bands in the sensorimotor and posterior parietal areas correlated with a more significant activity decrease in the contralateral SCM muscle, Findings from this study suggest that ST-related changes in the activity of sensorimotor and posterior parietal areas may restore dystonic posture and that both motor and sensory components contribute to the ST effect., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

Although restless legs syndrome (RLS) is a common neurological disorder, it remains poorly understood from both clinical and pathophysiological perspectives. RLS is classified among sleep-related movement disorders, namely, conditions characterized by simple, often stereotyped movements occurring during sleep. However, several clinical, neurophysiological and neuroimaging observations question this view. The aim of the present review is to summarize and query some of the current concepts (known knowns) and to identify open questions (known unknowns) on RLS pathophysiology. Based on several lines of evidence, we propose that RLS should be viewed as a disorder of sensorimotor interaction with a typical circadian pattern of occurrence, possibly arising from neurochemical dysfunction and abnormal excitability in different brain structures.

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.

We aimed to investigate salivary caffeine content, caffeine absorption and metabolism in Parkinson's disease (PD) and verify whether salivary caffeine can be used as a biomarker of PD. We enrolled 98 PD patients and 92 healthy subjects. Caffeine and its major metabolite, paraxanthine, were measured in saliva samples collected before and 4 h after the oral intake of caffeine (100 mg). We measured caffeine absorption as the normalized increase in caffeine levels, and caffeine metabolism as the paraxanthine/caffeine ratio. The Movement Disorder Society Unified Parkinson's Disease Rating Scale part III, the Hoehn & Yahr, the presence of motor complications, and levodopa equivalent dose (LED) were assessed and correlated with caffeine levels, absorption, and metabolism. The effects of demographic and environmental features possibly influencing caffeine levels were also investigated. Caffeine levels were decreased in patients with moderate/advanced PD, while caffeine levels were normal in patients with early and de-novo PD, unrelated to caffeine intake. Caffeine absorption and metabolism were normal in PD. Decreased salivary caffeine levels in PD were associated with higher disease severity, longer duration, and the presence of motor complications, no significant association was found with LED. Salivary caffeine decrease correlates with PD progression.

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.

Near-threshold tactile stimuli perception and somatosensory temporal discrimination threshold (STDT) are encoded in the primary somatosensory cortex (S1) and largely depend on alpha and beta S1 rhythm. Transcranial alternating current stimulation (tACS) is a non-invasive neurophysiological technique that allows cortical rhythm modulation. We investigated the effects of tACS delivered over S1 at alpha, beta, and gamma frequencies on near-threshold tactile stimuli perception and STDT, as well as phase-dependent tACS effects on near-threshold tactile stimuli perception in healthy subjects. In separate sessions, we tested the effects of different tACS montages, and tACS at the individualised S1 μ-alpha frequency peak, on STDT and near-threshold tactile stimuli perception. We found that tACS applied over S1 at alpha, beta, and gamma frequencies did not modify STDT or near-threshold tactile stimuli perception. Moreover, we did not detect effects of tACS phase or montage. Finally, tACS did not modify near-threshold tactile stimuli perception and STDT even when delivered at the individualised μ-alpha frequency peak. Our study showed that tACS does not alter near-threshold tactile stimuli or STDT, possibly due to the inability of tACS to activate deep S1 layers. Future investigations may clarify tACS effects over S1 in patients with focal dystonia, whose pathophysiology implicates increased STDT.

Background: Cervical dystonia (CD) is a focal dystonia characterized by sensorimotor integration abnormalities and proprioceptive dysfunction. Since proprioception is essential for bodily awareness, we hypothesized that CD patients may have an impairment in dystonic posture awareness. More information on this issue could be useful to better understand whether dystonic posture affects bodily perception in CD and could help in the development of specific rehabilitation strategies based on proprioceptive input manipulation to restore bodily awareness., Objectives: The aim of our study was to investigate dystonic posture and head tremor awareness in CD patients by comparing evaluations performed by CD patients with those performed by a neurologist expert in movement disorders., Methods: We enrolled 25 CD patients. We investigated dystonic posture and head tremor awareness in CD patients using a standardized protocol in which patients were asked to describe the type of dystonic pattern, both while viewing standardized images of different CD subtypes (torticollis, laterocollis, anterocollis, and retrocollis) and after watching a video recording of their dystonic posture and head tremor., Results: We found that 72% of CD patients correctly recognized their dystonic posture when viewing standardized images, whereas 84% of CD patients were able to identify their dystonic pattern when watching a video recording of themselves. CD patients also displayed a preserved awareness of their head tremor. We did not find any associations between dystonic pattern awareness and clinical or demographic features., Conclusion: Contrary to our hypothesis, the majority of CD patients have a preserved awareness of their dystonic pattern and tremor., (Copyright © 2020 Ferrazzano, Berardelli, Belvisi, De Bartolo, Di Vita, Conte and Fabbrini.)

(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.

Parkinson's disease (PD) is a neurodegenerative disorder whose pathogenesis depends on a combination of genetic and environmental factors. The aim of the present review was to provide an updated description of the findings emerging from prospective longitudinal cohort studies on the possible risk/protective factors underlying the development, progression and clinical subtypes of PD. We reviewed all the environmental, lifestyle, dietary, comorbid and pharmacological factors that have been investigated as possible modifiable protective/risk factors for PD by longitudinal studies. Only a few factors have the epidemiological evidence and the biological plausibility to be considered risk (pesticides, dairy products, β2-adrenoreceptor antagonists) or protective (smoking, caffeine and tea intake, physical activity, gout, vitamin E intake, non-steroidal anti-inflammatory drugs and β2-adrenoreceptor agonists) factors for PD. Caffeine intake and physical activity also seem to slow down the progression of the disease, thus representing good candidates for primary prevention and disease modifying strategies in PD. Possible modifiable risk factors of PD subtypes is almost unknown and this might depend on the uncertain biological and neuropathological reliability of clinical subtypes. The results of the present review suggest that only eleven risk/protective factors may be associated with the risk of PD. It may be possible to target some of these factors for preventive interventions aimed at reducing the risk of developing and the rate of progression of PD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Focal dystonia is a movement disorder characterized by involuntary muscle contractions that determine abnormal postures. The traditional hypothesis that the pathophysiology of focal dystonia entails a single structural dysfunction (i.e. basal ganglia) has recently come under scrutiny. The proposed network disorder model implies that focal dystonias arise from aberrant communication between various brain areas. Based on findings from animal studies, the role of the cerebellum has attracted increased interest in the last few years. Moreover, it has been increasingly reported that focal dystonias also include nonmotor disturbances, including sensory processing abnormalities, which have begun to attract attention. Current evidence from neurophysiological and neuroimaging investigations suggests that cerebellar involvement in the network and mechanisms underlying sensory abnormalities may have a role in determining the clinical heterogeneity of focal dystonias., Competing Interests: No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed., (Copyright: © 2020 Conte A et al.)

Introduction: We reviewed studies that assessed the treatment of psychiatric disturbances in Parkinson's disease and atypical parkinsonisms. Neuropsychiatric disturbances in these conditions are frequent and have a profound impact on quality of life of patients and of their caregivers. It is therefore important to be familiar with the appropriate pharmacological and non-pharmacological interventions for treating these disorders. Areas covered : The authors searched for papers in English in Pubmed using the following keywords: Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, depression, apathy, anxiety, fatigue, sleep disorders, obsessive compulsive disorders, psychosis, hallucinations, delusions, impulse control disorders. Expert opinion : In Parkinson's disease, depression may benefit from the optimization of dopaminergic therapy, from the use of antidepressants acting on both the serotoninergic and noradrenergic pathways and from cognitive behavioral therapy. Psychosis in Parkinson's disease may improve with the use of clozapine; the serotonin inverse agonist pimavanserin has been shown to be effective. Treatment of impulse control disorders is primarily based on the removal of dopamine agonists. No controlled studies have investigated the treatment of neuropsychiatric disorders in multiple system atrophy, progressive supranuclear palsy or corticobasal degeneration. Acethylcholinesterase inhibitors may be used to treat hallucinations in Lewy body dementia.

The aim of the study was to investigate the relationship between motor surround inhibition (mSI) and the modulation of somatosensory temporal discrimination threshold (STDT) induced by voluntary movement. Seventeen healthy volunteers participated in the study. To assess mSI, we delivered transcranial magnetic stimulation (TMS) single pulses to record motor evoked potentials (MEPs) from the right abductor digiti minimi (ADM; "surround muscle") during brief right little finger flexion. mSI was expressed as the ratio of ADM MEP amplitude during movement to MEP amplitude at rest. We preliminarily measured STDT values by assessing the shortest interval at which subjects were able to recognize a pair of electric stimuli, delivered over the volar surface of the right little finger, as separate in time. We then evaluated the STDT by using the same motor task used for mSI. mSI and STDT modulation were evaluated at the same time points during movement. mSI and STDT modulation displayed similar time-dependent changes during index finger movement. In both cases, the modulation was maximally present at the onset of the movement and gradually vanished over about 200 ms. Our study provides the first neurophysiological evidence about the relationship between mSI and tactile-motor integration during movement execution.

The somatosensory temporal discrimination threshold (STDT) has been used in recent years to investigate time processing of sensory information, but little is known about the physiological correlates of somatosensory temporal discrimination. The objective of this study was to investigate whether the time interval required to discriminate between two stimuli varies according to the number of stimuli in the task. We used the third-stimulus temporal discrimination threshold (ThirdDT), defined as the shortest time interval at which an individual distinguishes a third stimulus following a pair of stimuli delivered at the STDT. The STDT and ThirdDT were assessed in 31 healthy subjects. In a subgroup of 10 subjects, we evaluated the effects of the stimuli intensity on the ThirdDT. In a subgroup of 16 subjects, we evaluated the effects of S1 continuous theta-burst stimulation (S1-cTBS) on the STDT and ThirdDT. Results show that ThirdDT is shorter than STDT. We found a positive correlation between STDT and ThirdDT values. As long as the stimulus intensity was within the perceivable and painless range, it did not affect ThirdDT values. S1-cTBS significantly affected both STDT and ThirdDT, although the latter was affected to a greater extent and for a longer period of time. We conclude that the interval needed to discriminate between time-separated tactile stimuli is related to the number of stimuli used in the task. STDT and ThirdDT are encoded in S1, probably by a shared tactile temporal encoding mechanism whose performance rapidly changes during the perception process. ThirdDT is a new method to measure somatosensory temporal discrimination. NEW & NOTEWORTHY To investigate whether the time interval required to discriminate between stimuli varies according to changes in the stimulation pattern, we used the third-stimulus temporal discrimination threshold (ThirdDT). We found that the somatosensory temporal discrimination acuity varies according to the number of stimuli in the task. The ThirdDT is a new method to measure somatosensory temporal discrimination and a possible index of inhibitory activity at the S1 level., (Copyright © 2017 the American Physiological Society.)

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: The somatosensory temporal discrimination threshold (STDT) is defined as the shortest interval at which an individual recognizes two stimuli as asynchronous. Some evidence suggests that STDT depends on cortical inhibitory interneurons in the basal ganglia and in primary somatosensory cortex. Several studies have reported that the STDT in patients with dystonia is abnormal. No longitudinal studies have yet investigated whether STDT values in different forms of focal dystonia change during the course of the disease., Methods: We designed a follow-up study on 25 patients with dystonia (15 with blepharospasm and 10 with cervical dystonia) who were tested twice: upon enrolment and 8 years later. STDT values from dystonic patients at the baseline were also compared with those from a group of 30 age-matched healthy subjects., Results: Our findings show that the abnormally high STDT values observed in patients with focal dystonia remained unchanged at the 8-year follow-up assessment whereas disease severity worsened., Conclusions: Our observation that STDT abnormalities in dystonia remain unmodified during the course of the disease suggests that the altered activity of inhibitory interneurons-either at cortical or at subcortical level-responsible for the increased STDT does not deteriorate as the disease progresses.

The somatosensory temporal discrimination threshold (STDT) is the shortest interval at which an individual recognizes paired stimuli as separate in time. We investigated whether and how voluntary movement modulates STDT in healthy subjects. In 17 healthy participants, we tested STDT during voluntary index-finger abductions at several time-points after movement onset and during motor preparation. We then tested whether voluntary movement-induced STDT changes were specific for the body segment moved, depended on movement kinematics, on the type of movement or on the intensity for delivering paired electrical stimuli for STDT To understand the mechanisms underlying STDT modulation, we also tested STDT during motor imagery and after delivering repetitive transcranial magnetic stimulation to elicit excitability changes in the primary somatosensory cortex (S1). When tested on the moving hand at movement onset and up to 200 msec thereafter, STDT values increased from baseline, but during motor preparation remained unchanged. STDT values changed significantly during fast and slow index-finger movements and also, though less, during passive index-finger abductions, whereas during tonic index-finger abductions they remained unchanged. STDT also remained unchanged when tested in body parts other than those engaged in movement and during imagined movement. Nor did testing STDT at increased intensity influence movement-induced STDT changes. The cTBS-induced S1 cortical changes left movement-induced STDT changes unaffected. Our findings suggest that movement execution in healthy subjects may alter STDT processing., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

The present study describes the case of a 63-year-old woman presenting with headache, dizziness and vomiting due to a an ovoid mass in the left pre-bulbar cistern, apparently arising from the lower clivus and the foramen magnum. The clinical history revealed the subtotal removal of a right cerebellar low-grade glioma 15 years previously and subsequent conventional 60-Gy radiotherapy. Notably, following gross total resection, histopathological examination showed microscopic features that resulted in a diagnosis of anaplastic ependymoma. The patient underwent surgery to remove the mass and post-operative chemotherapy with temozolomide. A progressive improvement of neurological signs and symptoms was observed during the postoperative course. At the 6-month follow-up, the patient was free from clinical and radiological recurrence. The unusual features of this rare secondary brain tumor were the extrassial location in the posterior fossa, the unusual age-associated location of the histological subtype and the fact that it closely mimicked a skull-base meningioma.