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In March 2020, WHO declared Covid-19 outbreak pandemic. There has been increasing evidence that frail, old, multi-pathological patients are at greater risk of developing severe Covid-19 infection than younger, healthy ones. Covid-19's impact on Parkinson's Disease (PD) patients could be analysed through both the influence on PD patients' health and their risk of developing severe Covid-19, and the consequences of lockdown and restrictive measures on mental and cognitive health on both patients and caregivers. Moreover, there are critical issues to be considered about patients' care and management through an unprecedented time like this. One important issue to consider is physiotherapy, as most patients cannot keep exercising because of restrictive measures which has profoundly impacted on their health. Lastly, the relationship between PD and Sars-Cov2 may be even more complicated than it seems as some studies have hypothesized a possible Covid-19-induced parkinsonism. Hereby, we review the state of the art about the relationship between Covid-19 and Parkinson's Disease, focusing on each of these five points.

Objective To explore the potential rehabilitative effect of art therapy and its underlying mechanisms in Parkinson's disease (PD). Methods Observational study of eighteen patients with PD, followed in a prospective, open-label, exploratory trial. Before and after twenty sessions of art therapy, PD patients were assessed with the UPDRS, Pegboard Test, Timed Up and Go Test (TUG), Beck Depression Inventory (BDI), Modified Fatigue Impact Scale and PROMIS-Self-Efficacy, Montreal Cognitive Assessment, Rey-Osterrieth Complex Figure Test (RCFT), Benton Visual Recognition Test (BVRT), Navon Test, Visual Search, and Stop Signal Task. Eye movements were recorded during the BVRT. Resting-state functional MRI (rs-fMRI) was also performed to assess functional connectivity (FC) changes within the dorsal attention (DAN), executive control (ECN), fronto-occipital (FOC), salience (SAL), primary and secondary visual (V1, V2) brain networks. We also tested fourteen age-matched healthy controls at baseline. Results At baseline, PD patients showed abnormal visual-cognitive functions and eye movements. Analyses of rs-fMRI showed increased functional connectivity within DAN and ECN in patients compared to controls. Following art therapy, performance improved on Navon test, eye tracking, and UPDRS scores. Rs-fMRI analysis revealed significantly increased FC levels in brain regions within V1 and V2 networks. Interpretation Art therapy improves overall visual-cognitive skills and visual exploration strategies as well as general motor function in patients with PD. The changes in brain connectivity highlight a functional reorganization of visual networks.

Objective Sub-motor threshold 5 Hz repetitive paired associative stimulation (5 Hz-rPAS25ms) produces a long-lasting increase in corticospinal excitability. Assuming a spike-timing dependent plasticity-like (STDP-like) mechanism, we hypothesized that 5 Hz-rPAS at a shorter inter-stimulus interval (ISI) of 15 ms (5 Hz-rPAS15ms) would exert a lasting inhibitory effect on corticospinal excitability. Methods 20 healthy volunteers received two minutes of 5 Hz-rPAS15ms. Transcranial magnetic stimulation (TMS) was applied over the motor hotspot of the right abductor pollicis brevis muscle at 90% active motor threshold. Sub-motor threshold peripheral electrical stimulation was given to the left median nerve 15 ms before each TMS pulse. We assessed changes in mean amplitude of the unconditioned motor evoked potential (MEP), short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), long-latency afferent inhibition (LAI), and cortical silent period (CSP) before and for 60 minutes after 5-Hz rPAS15ms. Results Subthreshold 5-Hz rPAS15ms produced a 20–40% decrease in mean MEP amplitude along with an attenuation in SAI, lasting at least 60 minutes. A follow-up experiment revealed that MEP facilitation was spatially restricted to the target muscle. Conclusions Subthreshold 5-Hz rPAS15ms effectively suppresses corticospinal excitability. Together with the facilitatory effects of subthreshold 5-Hz rPAS25ms (Quartarone et al., J Physiol 2006;575:657–670), the results show that sub-motor threshold 5-Hz rPAS induces STDP-like bidirectional plasticity in the motor cortex. Significance The results of the present study provide a new short-time paradigm of long term depression (LTD) induction in human sensory-motor cortex.

Fatigue and cognitive difficulties are reported as the most frequently persistent symptoms in patients after mild SARS-CoV-2 infection. An extensive neurophysiological and neuropsychological assessment of such patients was performed focusing on motor cortex physiology and executive cognitive functions.Sixty-seven patients complaining of fatigue and/or cognitive difficulties after resolution of mild SARS-CoV-2 infection were enrolled together with 22 healthy controls (HCs). Persistent clinical symptoms were investigated by means of a 16-item questionnaire. Fatigue, exertion, cognitive difficulties, mood and 'well-being' were evaluated through self-administered tools. Utilizing transcranial magnetic stimulation of the primary motor cortex (M1) resting motor threshold, motor evoked potential amplitude, cortical silent period duration, short-interval intracortical inhibition, intracortical facilitation, long-interval intracortical inhibition and short-latency afferent inhibition were evaluated. Global cognition and executive functions were assessed with screening tests. Attention was measured with computerized tasks.Post COVID-19 patients reported a mean of 4.9 persistent symptoms, high levels of fatigue, exertion, cognitive difficulties, low levels of well-being and reduced mental well-being. Compared to HCs, patients presented higher resting motor thresholds, lower motor evoked potential amplitudes and longer cortical silent periods, concurring with reduced M1 excitability. Long-interval intracortical inhibition and short-latency afferent inhibition were also impaired, indicating altered GABAPatients with fatigue and cognitive difficulties following mild COVID-19 present altered excitability and neurotransmission within M1 and deficits in executive functions and attention.

Extensive work on movement-related beta oscillations (~13–30 Hz) over the sensorimotor areas in both humans and animals has demonstrated that sensorimotor beta power decreases during movement and transiently increases after movement. This beta power modulation has been interpreted as reflecting interactions between sensory and motor cortical areas with attenuation of sensory afferents during movement and their subsequent re-activation for internal models updating. More recent studies in neurologically normal subjects have demonstrated that this movement-related modulation as well as mean beta power at rest increase with practice and that previous motor learning enhances such increases. Conversely, patients with Parkinson's disease (PD) do not show such practice-related increases. Interestingly, a 2-h inactivity period without sleep can restore beta power values to baseline in normal subjects. Based on these results and on those of biochemical and electrophysiological studies in animals, we expand the current interpretation of beta activity and propose that the practice-related increases of beta power over sensorimotor areas are local indices of energy used for engaging plasticity-related activity. This paper provides some preliminary evidence in this respect linking findings of biochemical and electrophysiological studies in both humans and animals. This novel interpretation may explain the high level of beta power at rest, the deficient modulation during movement as well as the decreased skill formation in PD as resulting from deficiency in energy consumption, availability and regulation that are altered in this disease.

The subthalamic nucleus (STN) is commonly used as a surgical target for deep brain stimulation in movement disorders such as Parkinson's Disease. Tractography-derived connectivity-based parcellation (CBP) has been recently proposed as a suitable tool for non-invasive in vivo identification and pre-operative targeting of specific functional territories within the human STN. However, a well-established, accurate and reproducible protocol for STN parcellation is still lacking. The present work aims at testing the effects of different tractography-based approaches for the reconstruction of STN functional territories. We reconstructed functional territories of the STN on the high-quality dataset of 100 unrelated healthy subjects and on the test-retest dataset of the Human Connectome Project (HCP) repository. Connectivity-based parcellation was performed with a hypothesis-driven approach according to cortico-subthalamic connectivity, after dividing cortical areas into three groups: associative, limbic and sensorimotor. Four parcellation pipelines were compared, combining different signal modeling techniques (single-fiber vs multi-fiber) and different parcellation approaches (winner takes all parcellation vs fiber density thresholding). We tested these procedures on STN regions of interest obtained from three different, commonly employed, subcortical atlases. We evaluated the pipelines both in terms of between-subject similarity, assessed on the cohort of 100 unrelated healthy subjects, and of within-subject similarity, using a second cohort of 44 subjects with available test-retest data. We found that each parcellation provides converging results in terms of location of the identified parcels, but with significative variations in size and shape. All pipelines obtained very high within-subject similarity, with tensor-based approaches outperforming multi-fiber pipelines. On the other hand, higher between-subject similarity was found with multi-fiber signal modeling techniques combined with fiber density thresholding. We suggest that a fine-tuning of tractography-based parcellation may lead to higher reproducibility and aid the development of an optimized surgical targeting protocol.

Background: Brain tumors can cause different changes in excitation and inhibition at the neuronal network level. These changes can be generated from mechanical and cellular alterations, often manifesting clinically as seizures.Objective/Hypothesis: The effects of brain tumors on cortical excitability (CE) have not yet been well-evaluated. The aim of the current study was to further investigate cortical–cortical and cortical–spinal excitability in patients with brain tumors using a more extensive transcranial magnetic stimulation protocol.Methods: We evaluated CE on 12 consecutive patients with lesions within or close to the precentral gyrus, as well as in the subcortical white matter motor pathways. We assessed resting and active motor threshold, short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), long-latency afferent inhibition, cortical silent period, and interhemispheric inhibition.Results: CE was reduced in patients with brain tumors than in healthy controls. In addition, SICI, ICF, and SAI were lower in the affected hemisphere compared to the unaffected and healthy controls.Conclusions: CE is abnormal in hemispheres affected by brain tumors. Further studies are needed to determine if CE is related with motor impairment.

This article is based on a consensus conference, promoted and supported by the International Federation of Clinical Neurophysiology (IFCN), which took place in Siena (Italy) in October 2018. The meeting intended to update the ten-year-old safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical settings (Rossi et al., 2009). Therefore, only emerging and new issues are covered in detail, leaving still valid the 2009 recommendations regarding the description of conventional or patterned TMS protocols, the screening of subjects/patients, the need of neurophysiological monitoring for new protocols, the utilization of reference thresholds of stimulation, the managing of seizures and the list of minor side effects. New issues discussed in detail from the meeting up to April 2020 are safety issues of recently developed stimulation devices and pulse configurations; duties and responsibility of device makers; novel scenarios of TMS applications such as in the neuroimaging context or imaging-guided and robot-guided TMS; TMS interleaved with transcranial electrical stimulation; safety during paired associative stimulation interventions; and risks of using TMS to induce therapeutic seizures (magnetic seizure therapy). An update on the possible induction of seizures, theoretically the most serious risk of TMS, is provided. It has become apparent that such a risk is low, even in patients taking drugs acting on the central nervous system, at least with the use of traditional stimulation parameters and focal coils for which large data sets are available. Finally, new operational guidelines are provided for safety in planning future trials based on traditional and patterned TMS protocols, as well as a summary of the minimal training requirements for operators, and a note on ethics of neuroenhancement.

More than half of patients who recover from COVID-19 experience fatigue. We studied fatigue using neuropsychological and neurophysiological investigations in post-COVID-19 patients and healthy subjects. Neuropsychological assessment included: Fatigue Severity Scale (FSS), Fatigue Rating Scale, Beck Depression Inventory, Apathy Evaluation Scale, cognitive tests, and computerized tasks. Neurophysiological examination was assessed before (PRE) and 2 min after (POST) a 1-min fatiguing isometric pinching task and included: maximum compound muscle action potential (CMAP) amplitude in first dorsal interosseous muscle (FDI) following ulnar nerve stimulation, resting motor threshold, motor evoked potential (MEP) amplitude and silent period (SP) duration in right FDI following transcranial magnetic stimulation of the left motor cortex. Maximum pinch strength was measured. Perceived exertion was assessed with the Borg-Category-Ratio scale. Patients manifested fatigue, apathy, executive deficits, impaired cognitive control, and reduction in global cognition. Perceived exertion was higher in patients. CMAP and MEP were smaller in patients both PRE and POST. CMAP did not change in either group from PRE to POST, while MEP amplitudes declined in controls POST. SP duration did not differ between groups PRE, increased in controls but decreased in patients POST. Patients' change of SP duration from PRE to POST was negatively correlated to FSS. Abnormal SP shortening and lack of MEP depression concur with a reduction in post-exhaustion corticomotor inhibition, suggesting a possible GABAB-ergic dysfunction. This impairment might be related to the neuropsychological alterations. COVID-19-associated inflammation might lead to GABAergic impairment, possibly representing the basis of fatigue and explaining apathy and executive deficits., Highlights • Neuropsychological and neurophysiological features of fatigue were studied in post-COVID-19 patients. • Apathy, deficits in executive functions and reduction in global cognition were found. • Abnormal shortening of cortical silent period and lack of MEP depression were demonstrated after a fatiguing task. • Disruption of post-exhaustion corticomotor inhibition suggests GABA-ergic dysfunction. • GABA-ergic impairment might subtend fatigue and executive deficits in COVID-19.

Internal and external segments of globus pallidus (GP) exert different functions in basal ganglia circuitry, despite their main connectional systems share the same topographical organization, delineating limbic, associative, and sensorimotor territories. The identification of internal GP sensorimotor territory has therapeutic implications in functional neurosurgery settings. This study is aimed at assessing the spatial coherence of striatopallidal, subthalamopallidal, and pallidothalamic pathways by using tractography‐derived connectivity‐based parcellation (CBP) on high quality diffusion MRI data of 100 unrelated healthy subjects from the Human Connectome Project. A two‐stage hypothesis‐driven CBP approach has been carried out on the internal and external GP. Dice coefficient between functionally homologous pairs of pallidal maps has been computed. In addition, reproducibility of parcellation according to different pathways of interest has been investigated, as well as spatial relations between connectivity maps and existing optimal stimulation points for dystonic patients. The spatial organization of connectivity clusters revealed anterior limbic, intermediate associative and posterior sensorimotor maps within both internal and external GP. Dice coefficients showed high degree of coherence between functionally similar maps derived from the different bundles of interest. Sensorimotor maps derived from the subthalamopallidal pathway resulted to be the nearest to known optimal pallidal stimulation sites for dystonic patients. Our findings suggest that functionally homologous afferent and efferent connections may share similar spatial territory within the GP and that subcortical pallidal connectional systems may have distinct implications in the treatment of movement disorders., The identification of internal globus pallidus (GP) sensorimotor territory has therapeutic implications in functional neurosurgery settings. This study is aimed at assessing the spatial coherence of striatopallidal, subthalamopallidal and pallidothalamic pathways by using tractography‐derived connectivity‐based parcellation. Our results suggest that the general topographical organization of connectivity parcels is highly consistent across the internal and external GP, regardless the bundle of interest, corroborating the hypothesis that different pathways, running parallel and in series to one other, may share the same spatial organization pattern. Indeed, we found high similarity among functionally homologous connectivity maps derived from the striatopallidal, subthalamopallidal and pallidothalamic tracts. In other words, we show neuroimaging evidences suggesting the presence of partially segregated yet integrated functional territories within the GP, derived from connectivity patterns that maintain a consistent topographical arrangement throughout the entire cortico‐basal ganglia‐thalamo‐cortical circuitry.

A group of European experts reappraised the guidelines on the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) previously published in 2014 [Lefaucheur et al., Clin Neurophysiol 2014;125:2150-206]. These updated recommendations take into account all rTMS publications, including data prior to 2014, as well as currently reviewed literature until the end of 2018. Level A evidence (definite efficacy) was reached for: high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the painful side for neuropathic pain; HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC) using a figure-of-8 or a Hl-coil for depression; low-frequency (LF) rTMS of contralesional M1 for hand motor recovery in the post-acute stage of stroke. Level B evidence (probable efficacy) was reached for: HF-rTMS of the left M1 or DLPFC for improving quality of life or pain, respectively, in fibromyalgia; HF-rTMS of bilateral M1 regions or the left DLPFC for improving motor impairment or depression, respectively, in Parkinson's disease; HF-rTMS of ipsilesional M1 for promoting motor recovery at the post-acute stage of stroke; intermittent theta burst stimulation targeted to the leg motor cortex for lower limb spasticity in multiple sclerosis; HF-rTMS of the right DLPFC in posttraumatic stress disorder; LF-rTMS of the right inferior frontal gyrus in chronic post-stroke non-fluent aphasia; LF-rTMS of the right DLPFC in depression; and bihemispheric stimulation of the DLPFC combining right-sided LF-rTMS (or continuous theta burst stimulation) and left-sided HF-rTMS (or intermittent theta burst stimulation) in depression. Level A/B evidence is not reached concerning efficacy of rTMS in any other condition. The current recommendations are based on the differences reached in therapeutic efficacy of real vs. sham rTMS protocols, replicated in a sufficient number of independent studies. This does not mean that the benefit produced by rTMS inevitably reaches a level of clinical relevance. (C) 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.

When referring to the study of Rutherford et al. (2015) on short- and long-term effects of rTMS in Alzheimer's disease, we erroneously stated in our article (Lefaucheur et al., 2020) that a clinical benefit on cognitive performance (tested by the Montreal Cognitive Assessment) was observed at weeks 2–3, only in the real stimulation condition during an initial sham-controlled 4-week period of treatment, and that then this benefit was prolonged by “2 additional weeks” of open-label real rTMS. In fact, this extended open-label treatment was administered for up to 19 months in multiple 2-week blocks with 2–7 months intervals between blocks and was not limited to a single additional 2-week block of treatment immediately following the original 4 weeks of treatment. Therefore, the results of that open-label extended follow-up study support the value of long-term maintenance treatment using multiple rTMS sessions rather than be interpreted as short-term 2-week extension.

Objective: To investigate the mechanism subtending the analgesic effect of high frequency non-painful somatosensory stimulation. Methods: Laser evoked potentials (LEPs) and laser-pain rating were obtained from healthy subjects to stimulation of different parts of the body. LEPs were recorded at baseline and during non-painful electrical stimulation of the superficial branch of the right radial nerve (RRES). Results: RRES reduced N2/P2 LEP amplitude to right radial (F(8,10) = 82.4, p < 0.001), left radial (F(8,10) = 22.2, p < 0.001), and right ulnar (F(8,10) = 7.2, p = 0.008) stimulation, while the N2/P2 amplitude to left ulnar territory stimulation remained unchanged (F(8,10) = 3.6, p = 0.07). The laser-pain rating was reduced by RRES to bilateral radial territory stimulation (p < 0.05). In a control experiment, laser-pain rating and LEPs to left foot stimulation were not modified by RRES (p > 0.05). Conclusions: Our study confirms that the non-nociceptive afferents dampen the nociceptive input. The spatial pattern of this interaction suggests that, when conditioning higher frequency non-painful stimulation is used, the inhibition takes place at the spinal cord. Significance: Our experimental design reproduces what happens when non-painful somatosensory stimuli are used to reduce pain, such as rubbing a wound or during transcutaneous electrical nerve stimulation. Therefore, in these situations the analgesia is likely to occur at the spinal cord level.

Levodopa-induced dyskinesias are motor complications following long term dopaminergic therapy in Parkinson's disease (PD). Impaired brain plasticity resulting in the creation of aberrant motor maps intended to encode normal voluntary movement is proposed to result in the development of dyskinesias. Traditionally, the various nodes in the motor network like the striato-cortical and the cerebello-thalamic loops were thought to function independent of each other with little communication among them. Anatomical evidence from primates revealed the existence of reciprocal loops between the basal ganglia and the cerebellum providing an anatomical basis for communication between the motor network loops. Dyskinetic PD patients reveal impaired brain plasticity within the motor cortex which may be modulated by cortico-cortical, cerebello-cortical or striato-cortical connections. In this article, we review the evidence for altered plasticity in the multicomponent motor network in the context of levodopa induced dyskinesias in PD. Current evidence suggests a pivotal role for the cerebellum in the larger motor network with the ability to integrate sensorimotor information and independently influence multiple nodes in this network. Targeting the cerebellum seems to be a justified approach for future interventions aimed at attenuating levodopa-induced dyskinesias.

Background Understanding the topographical organization of the cortico-basal ganglia circuitry is of pivotal importance because of the spreading of techniques such as DBS and, more recently, MR-guided focused ultrasound for the treatment of movement disorders. A growing body of evidence has described both direct cortico- and dento-pallidal connections, although the topographical organization in vivo of these pathways in the human brain has never been reported. Objective To investigate the topographical organization of cortico- and dento-pallidal pathways by means of diffusion MRI tractography and connectivity based parcellation. Methods High-quality data from 100 healthy subjects from the Human Connectome Project repository were utilized. Constrained spherical deconvolution-based tractography was used to reconstruct structural cortico- and dento-pallidal connectivity. Connectivity-based parcellation was performed with a hypothesis-driven approach at three different levels: functional regions (limbic, associative, sensorimotor, and other), lobes, and gyral subareas. Results External globus pallidus segregated into a ventral associative cluster, a dorsal sensorimotor cluster, and a caudal "other" cluster on the base of its cortical connectivity. Dento-pallidal connections clustered only in the internal globus pallidus, where also associative and sensorimotor clusters were identified. Lobar parcellation revealed the presence in the external globus pallidus of dissociable clusters for each cortical lobe (frontal, parietal, temporal, and occipital), whereas in internal globus pallidus only frontal and parietal clusters were found out. Conclusion We mapped the topographical organization of both internal and external globus pallidus according to cortical and cerebellar connections. These anatomical data could be useful in DBS, radiosurgery and MR-guided focused ultrasound targeting for treating motor and nonmotor symptoms in movement disorders. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

The claustrum is a thin grey matter structure which is involved in a wide brain network. Previous studies suggested a link between claustrum and Parkinson’s Disease (PD), showing how α-synuclein pathology may affect claustral neurons as well as how α-synuclein immunoreactivity may correlate with the onset of cognitive dysfunctions. Our aim is to investigate, via diffusion MRI, claustral structural network changes in drug naive PD patients, with the goal to understand whether such changes may contribute to cognitive decline in PD. 15 drug naive PD patients and 15 age-matched controls were enrolled; MR protocol was performed on a 3T scanner. Whole brain probabilistic tractography was obtained using Constrained Spherical Deconvolution (CSD) diffusion model. Connectivity matrices were estimated based on a robust anatomical parcellation of structural T1w images. In PD group, impaired subnetworks were correlated with psychological examinations. We found decreased claustral connectivity in PD patients compared to controls, especially with areas mainly involved in visuomotor and attentional systems. Moreover, we found a positive correlation between MoCA and density of pathways connecting ipsilaterally claustrum to left (r = 0.578, p = 0.021) and right (r = 0.640, p = 0.020) Pars Orbitalis. Our results support the hypothesis of claustral involvement in cognitive decline in drug naive PD patients.

Over the last decades, psychophysical and electrophysiological studies in patients and animal models of Parkinson’s disease (PD), have consistently revealed a number of visual abnormalities. In particular, specific alterations of contrast sensitivity curves, electroretinogram (ERG), and visual-evoked potentials (VEP), have been attributed to dopaminergic retinal depletion. However, fundamental mechanisms of cortical visual processing, such as normalization or “gain control” computations, have not yet been examined in PD patients. Here, we measured electrophysiological indices of gain control in both space (surround suppression) and time (sensory adaptation) in PD patients based on steady-state VEP (ssVEP). Compared with controls, patients exhibited a significantly higher initial ssVEP amplitude that quickly decayed over time, and greater relative suppression of ssVEP amplitude as a function of surrounding stimulus contrast. Meanwhile, EEG frequency spectra were broadly elevated in patients relative to controls. Thus, contrary to what might be expected given the reduced contrast sensitivity often reported in PD, visual neural responses are not weaker; rather, they are initially larger but undergo an exaggerated degree of spatial and temporal gain control and are embedded within a greater background noise level. These differences may reflect cortical mechanisms that compensate for dysfunctional center-surround interactions at the retinal level.

Several techniques and protocols of non-invasive transcranial brain stimulation (NIBS), including transcranial magnetic and electrical stimuli, have been developed in the past decades. These techniques can induce long lasting changes in cortical excitability by promoting synaptic plasticity and thus may represent a therapeutic option in neuropsychiatric disorders. On the other hand, despite these techniques have become popular, the fragility and variability of the after effects are the major challenges that non-invasive transcranial brain stimulation currentlyfaces. Several factors may account for such a variability such as biological variations, measurement reproducibility, and the neuronal state of the stimulated area. One possible strategy, to reduce this variability is to monitor the neuronal state in real time using EEG and trigger TMS pulses only at pre-defined state. In addition, another strategy under study is to use the spaced application of multiple NIBS protocols within a session to improve the reliability and extend the duration of NIBS effects. Further studies, although time consuming, are required for improving the so far limited effect sizes of NIBS protocols for treatment of neurological or psychiatric disorders.

Objective: we investigated the effect of anodal transcranial direct current stimulation (tDCS) applied over the pharyngeal motor area in dysphagia associated with multiple sclerosis (MS). Methods: Eighteen MS patients with dysphagia associated with brainstem involvement were randomized to receive either “real” or “sham” tDCS. Primary outcome: The Penetration/Aspiration Scale (PAS). Secondary outcomes: changes in electromyographic (EMG) parameters and pharyngeal cortical motor evoked potentials (MEPs). Patients were evaluated at baseline (T0), at the end of 5-session cycle of tDCS stimulations (T1), after two (T2), and four (T3) weeks. Results: the PAS values were significantly lower in the active group than in “sham” group at T1, and at T3. Over the post-stimulation periods, PAS significantly improved only in the “real” group. As regards the secondary outcomes, we observed a statistically significant difference between the 2 groups only in the MEPs amplitude at T1. The comparison between baseline and each of the post-stimulation times showed significant differences only of the “real” group across all the secondary parameters. Conclusions: Our findings support a beneficial effect of anodal tDCS applied to the pharyngeal motor cortex in MS-associated dysphagia. Significance: Considering its safety and efficacy, tDCS may represent an important resource in MS-associated dysphagia.

Tendon vibration of a limb elicits illusory movements in the direction that the vibrated muscle would be stretched, followed by a transient perception of movement in the opposite direction, that was demonstrated to correspond to a "cortical" aftereffect (Goodwin et al. Science 175:1382-1384, 1972). Primary motor cortex (M1) excitability of the non-vibrated antagonist muscle of the vibrated muscle increased during vibration and decreased thereafter. The cortical aftereffect is of interest when considering the possibility to use tendon vibration in rehabilitation for restoring unbalance activity between antagonistic muscles but, due to its short-lasting duration, has not been explored so far. We investigated the possibility to consolidate the cortical aftereffect by combining tendon vibration with a concomitant high-frequency 5-Hz repetitive transcranial magnetic stimulation (rTMS) protocol. The distal tendon of the flexor carpi radialis muscle (FCR) was vibrated and concomitantly a 2-min 5-Hz rTMS protocol was administered on the left hemi-scalp hot spot of the vibrated FCR or its antagonist muscle (extensor carpi radialis (ECR)). We found that this protocol induced a pattern of unbalanced M1 excitability between vibrated muscle and its antagonist with increased excitability of the FCR and decreased excitability of ECR cortical areas, which persisted up to 30 min.

Background Movement disorders associated with complex regional pain syndrome type I have been a subject of controversy over the last 10 years regarding their nature and pathophysiology, with an intense debate about the functional (psychogenic) nature of this disorder. The aim of this study was to test sensorimotor plasticity and cortical excitability in patients with complex regional pain syndrome type I who developed a fixed posture of the hand. Methods Ten patients with complex regional pain syndrome type I in the right upper limb and a fixed posture of the hand (disease duration less than 24 months) and 10 age-matched healthy subjects were enrolled. The following parameters of corticospinal excitability were recorded from the abductor pollicis brevis muscle of both hands by transcranial magnetic stimulation: resting and active motor thresholds, short-interval intracortical inhibition and facilitation, cortical silent period, and short- and long-latency afferent inhibition. Sensorimotor plasticity was tested using the paired associative stimulation protocol. Results Short-interval intracortical inhibition and long-latency afferent inhibition were reduced only in the affected right hand of patients compared with control subjects. Sensorimotor plasticity was comparable to normal subjects, with a preserved topographic specificity. Conclusions Our data support the view that motor disorder in complex regional pain syndrome type I is not associated with abnormal sensorimotor plasticity, and it shares pathophysiological abnormalities with functional (psychogenic) dystonia rather than with idiopathic dystonia. © 2016 International Parkinson and Movement Disorder Society

According to the classical view, the cerebellum has long been confined to motor control physiology; however, it has now become evident that it exerts several non-somatic features other than the coordination of movement and is engaged also in the regulation of cognition and emotion. In a previous diffusion-weighted imaging-constrained spherical deconvolution (CSD) tractography study, we demonstrated the existence of a direct cerebellum-hippocampal pathway, thus reinforcing the hypothesis of the cerebellar role in non-motor domains. However, our understanding of limbic-cerebellar interconnectivity in humans is rather sparse, primarily due to the intrinsic limitation in the acquisition of in vivo tracing. Here, we provided tractographic evidences of connectivity patterns between the cerebellum and mammillary bodies by using whole-brain CSD tractography in 13 healthy subjects. We found both ipsilateral and contralateral connections between the mammillary bodies, cerebellar cortex, and dentate nucleus, in line with previous studies performed in rodents and primates. These pathways could improve our understanding of cerebellar role in several autonomic functions, visuospatial orientation, and memory and may shed new light on neurodegenerative diseases in which clinically relevant impairments in navigational skills or memory may become manifest at early stages.

In the last decades, a number of Diffusion Weighted Imaging (DWI) based techniques have been developed to study non-invasively human brain tissues, especially white matter (WM). In this context, Constrained Spherical Deconvolution (CSD) is recognized as being able to accurately characterize water molecules displacement, as they emerge from the observation of MR diffusion weighted (MR-DW) images. CSD is suggested to be applied on MR-DW datasets consisting of b-values around 3,000 s/mm2 and at least 45 unique diffusion weighting directions. Below such technical requirements, Diffusion Tensor Imaging (DT) remains the most widely accepted model. Unlike CSD, DTI is unable to resolve complex fiber geometries within the brain, thus affecting related tissues quantification. In addition, thanks to CSD, an index called Apparent Fiber Density (AFD) can be measured to estimate intra-axonal volume fraction within WM. In standard clinical settings, diffusion based acquisitions are well below such technical requirements. Therefore, in this study we wanted to extensively compare CSD and DTI model outcomes on really low demanding MR-DW datasets, i.e., consisting of a single shell (b-value = 1,000 s/mm2) and only 30 unique diffusion encoding directions. To this end, we performed deterministic and probabilistic tractographic reconstruction of two major WM pathways, namely the Corticospinal Tract and the Arcuate Fasciculus. We estimated and analyzed tensor based features as well as, for the first time, AFD interpretability in our data. By performing multivariate statistics and tract-based ROI analysis, we demonstrate that WM quantification is affected by both the diffusion model and threshold applied to noisy tractographic maps. Consistently with existing literature, we showed that CSD outperforms DTI even in our scenario. Most importantly, for the first time we address the problem of accuracy and interpretation of AFD in a low-demanding DW setup, and show that it is still a biological meaningful measure for the analysis of intra-axonal volume even in clinical settings.

In the last decades, a number of Diffusion Weighted Imaging (DWI) based techniques have been developed to study non-invasively human brain tissues, especially white matter (WM). In this context, Constrained Spherical Deconvolution (CSD) is recognized as being able to accurately characterize water molecules displacement, as they emerge from the observation of MR diffusion weighted (MR-DW) images. CSD is suggested to be applied on MR-DW datasets consisting of b-values around 3,000 s/mm2 and at least 45 unique diffusion weighting directions. Below such technical requirements, Diffusion Tensor Imaging (DT) remains the most widely accepted model. Unlike CSD, DTI is unable to resolve complex fiber geometries within the brain, thus affecting related tissues quantification. In addition, thanks to CSD, an index called Apparent Fiber Density (AFD) can be measured to estimate intra-axonal volume fraction within WM. In standard clinical settings, diffusion based acquisitions are well below such technical requirements. Therefore, in this study we wanted to extensively compare CSD and DTI model outcomes on really low demanding MR-DW datasets, i.e., consisting of a single shell (b-value = 1,000 s/mm2) and only 30 unique diffusion encoding directions. To this end, we performed deterministic and probabilistic tractographic reconstruction of two major WM pathways, namely the Corticospinal Tract and the Arcuate Fasciculus. We estimated and analyzed tensor based features as well as, for the first time, AFD interpretability in our data. By performing multivariate statistics and tract-based ROI analysis, we demonstrate that WM quantification is affected by both the diffusion model and threshold applied to noisy tractographic maps. Consistently with existing literature, we showed that CSD outperforms DTI even in our scenario. Most importantly, for the first time we address the problem of accuracy and interpretation of AFD in a low-demanding DW setup, and show that it is still a biological meaningful measure for the analysis of intra-axonal volume even in clinical settings.

Background. Surround inhibition is a system that sharpens sensation by creating an inhibitory zone around the central core of activation. In the motor system, this mechanism probably contributes to the selection of voluntary movements, and it seems to be lost in dystonia. Objectives. To explore if sensory information is abnormally processed and integrated in focal hand dystonia (FHD) and if surround inhibition phenomena are operating during sensory-motor plasticity and somatosensory integration in normal humans and in patients with FHD. Methods. We looked at the MEP facilitation obtained after 5 Hz repetitive paired associative stimulation of median (PAS M), ulnar (PAS U), and median + ulnar nerve (PAS MU) stimulation in 8 normal subjects and 8 FHD. We evaluated the ratio MU/(M + U) ∗ 100 and the spatial and temporal somatosensory integration recording the somatosensory evoked potentials (SEPs) evoked by a dual nerve input. Results. FHD had two main abnormalities: first, the amount of facilitation was larger than normal subjects; second, the spatial specificity was lost. The MU/(M + U) ∗ 100 ratio was similar in healthy subjects and in FHD patients, and the somatosensory integration was normal in this subset of patients. Conclusions. The inhibitory integration of somatosensory inputs and the somatosensory inhibition are normal in patients with focal dystonia as well as lateral surrounding inhibition phenomena during sensory-motor plasticity in FHD.

Sativex is an emergent treatment option for spasticity in patients affected by multiple sclerosis (MS). This oromucosal spray, acting as a partial agonist at cannabinoid receptors, may modulate the balance between excitatory and inhibitory neurotransmitters, leading to muscle relaxation that is in turn responsible for spasticity improvement. Nevertheless, since the clinical assessment may not be sensitive enough to detect spasticity changes, other more objective tools should be tested to better define the real drug effect. The aim of our study was to investigate the role of Sativex in improving spasticity and related symptomatology in MS patients by means of an extensive neurophysiological assessment of sensory-motor circuits. To this end, 30 MS patients underwent a complete clinical and neurophysiological examination, including the following electrophysiological parameters: motor threshold, motor evoked potentials amplitude, intracortical excitability, sensory-motor integration, andHmax/Mmaxratio. The same assessment was applied before and after one month of continuous treatment. Our data showed an increase of intracortical inhibition, a significant reduction of spinal excitability, and an improvement in spasticity and associated symptoms. Thus, we can speculate that Sativex could be effective in reducing spasticity by means of a double effect on intracortical and spinal excitability.

Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are non-invasive methods for stimulating cortical neurons that have been increasingly used in the neurology realm and in the neurosciences applied to movement disorders. In addition, these tools have the potential to be delivered as clinically therapeutic approach. Despite several studies support this hypothesis, there are several limitations related to the extreme variability of the stimulation protocols, clinical enrolment and variability of rTMS and tDCS after effects that make clinical interpretation very difficult. Aim of the present study will be to critically discuss the state of art therapeutically applications of rTMS and tDCS in dystonia.

Objective The objective of this study was to explore the short-term effects of repetitive transcranial magnetic stimulation (rTMS) on action myoclonus. Methods Nine patients with Unverricht–Lundborg (EPM1) progressive myoclonus epilepsy type underwent two series of 500 stimuli at 0.3 Hz through round coil twice a day for five consecutive days. Clinical and neurophysiological examinations were performed two hours before starting the first rTMS session and two hours after the end of the last rTMS session. Results Eight patients completed the protocol; one discontinued because of a transient increase in spontaneous jerks. The unified myoclonus rating scale indicated a 25% reduction in posttreatment myoclonus with action score associated with an increase in the cortical motor threshold and lengthening of the cortical silent period (CSP). The decrease in the myoclonus with action scores correlated with the prolongation of CSP. Conclusions Repetitive transcranial magnetic stimulation can be safely used in patients with EPM1, improves action myoclonus, and partially restores deficient cortical inhibition.

Dystonia can be seen in a number of different phenotypes that may arise from different etiologies. The pathophysiological substrate of dystonia is related to three lines of research. The first postulate a loss of inhibition which may account for the excess of movement and for the overflow phenomena. A second abnormality is sensory dysfunction which is related to the mild sensory complaints in patients with focal dystonias and may be responsible for some of the motor dysfunction. Finally, there are strong pieces of evidence from animal and human studies suggesting that alterations of synaptic plasticity characterized by a disruption of homeostatic plasticity, with a prevailing facilitation of synaptic potentiation may play a pivotal role in primary dystonia. These working hypotheses have been generalized in all form of dystonia. On the other hand, several pieces of evidence now suggest that the pathophysiology may be slightly different in the different types of dystonia. Therefore, in the present review, we would like to discuss the neural mechanisms underlying the different forms of dystonia to disentangle the different weight and role of environmental and predisposing factors.

Recently we found that modulation depth of beta power during movement increases with practice over sensory-motor areas in normal subjects but not in patients with Parkinson’s disease (PD). As such changes might reflect use-dependent modifications, we concluded that reduction of beta enhancement in PD represents saturation of cortical plasticity. A few questions remained open: What is the relation between these EEG changes and retention of motor skills? Would a second task exposure restore beta modulation enhancement in PD? Do practice-induced increases of beta modulation occur within each block? We thus recorded EEG in patients with PD and age-matched controls in two consecutive days during a forty-minute reaching task divided in fifteen blocks of 56 movements each. The results confirmed that, with practice, beta modulation depth over the contralateral sensory-motor area significantly increased across blocks in controls but not in PD, while performance improved in both groups without significant correlations between behavioral and EEG data. The same changes were seen the following day in both groups. Also, beta modulation increased within each block with similar values in both groups and such increases were partially transferred to the successive block in controls, but not in PD. Retention of performance improvement was present in the controls but not in the patients and correlated with the increase in day 1 modulation depth. Therefore, the lack of practice-related increase beta modulation in PD is likely due to deficient potentiation mechanisms that permit between-block saving of beta power enhancement and trigger mechanisms of memory formation.

Objective: Investigation of spatial and temporal cognitive processing in Idiopathic Cervical Dystonia (CD) by means of specific tasks based on perception in time and space domains of visual and auditory stimuli. Background: Previous psychophysiological studies have investigated temporal and spatial characteristics of neural processing of sensory stimuli (mainly somatosensorial and visual), whereas the definition of such processing at higher cognitive level has not been sufficiently addressed. The impairment of time and space processing is likely driven by basal ganglia dysfunction. However, other cortical and subcortical areas, including cerebellum, may also be involved. Methods: We tested twenty-one subjects with Cervical Dystonia and twenty-two age-matched healthy controls with four recognition tasks exploring visuo-spatial, audio-spatial, visuo-temporal and audio-temporal processing. Dystonic subjects were subdivided in three groups according to the head movement pattern type (lateral: Laterocolis, rotation: Torticollis) as well as the presence of tremor (Tremor). Results: We found significant alteration of spatial processing in Laterocollis subgroup compared to controls, whereas impairment of temporal processing was observed in Torticollis subgroup compared to controls. Conclusions: Our results suggest that Dystonia is associated with a dysfunction of temporal and spatial processing for visual and auditory stimuli that could underlie the well-known abnormalities in sequence learning. Moreover, we suggest that different movement pattern type might lead to different dysfunctions at cognitive level within dystonic population.

Despite increasing evidence suggesting the cerebellum works in concert with the cortex and basal ganglia, the nature of the reciprocal interactions between these three brain regions remains unclear. This consensus paper gathers diverse recent views on a variety of important roles played by the cerebellum within the cerebello-basal ganglia-thalamo-cortical system across a range of motor and cognitive functions. The paper includes theoretical and empirical contributions, which cover the following topics: recent evidence supporting the dynamical interplay between cerebellum, basal ganglia, and cortical areas in humans and other animals; theoretical neuroscience perspectives and empirical evidence on the reciprocal influences between cerebellum, basal ganglia, and cortex in learning and control processes; and data suggesting possible roles of the cerebellum in basal ganglia movement disorders. Although starting from different backgrounds and dealing with different topics, all the contributors agree that viewing the cerebellum, basal ganglia, and cortex as an integrated system enables us to understand the function of these areas in radically different ways. In addition, there is unanimous consensus between the authors that future experimental and computational work is needed to understand the function of cerebellar-basal ganglia circuitry in both motor and non-motor functions. The paper reports the most advanced perspectives on the role of the cerebellum within the cerebello-basal ganglia-thalamo-cortical system and illustrates other elements of consensus as well as disagreements and open questions in the field.

The final goal of motor learning, a complex process that includes both implicit and explicit (or declarative) components, is the optimization and automatization of motor skills. Motor learning involves different neural networks and neurotransmitters systems depending on the type of task and on the stage of learning. After the first phase of acquisition, a motor skill goes through consolidation (i.e., becoming resistant to interference) and retention, processes in which sleep and long-term potentiation seem to play important roles. The studies of motor learning in Parkinson's disease have yielded controversial results that likely stem from the use of different experimental paradigms. When a task’s characteristics, instructions, context, learning phase and type of measures are taken into consideration, it is apparent that, in general, only learning that relies on attentional resources and cognitive strategies is affected by PD, in agreement with the finding of a fronto-striatal deficit in this disease. Levodopa administration does not seem to reverse the learning deficits in PD, while deep brain stimulation of either globus pallidus or subthalamic nucleus appears to be beneficial. Finally and most importantly, patients with PD often show a decrease in retention of newly learned skill, a problem that is present even in the early stages of the disease. A thorough dissection and understanding of the processes involved in motor learning is warranted to provide solid bases for effective medical, surgical and rehabilitative approaches in PD.

The original protocol of Paired Associative Stimulation (PAS) in humans implies repetitive cortical and peripheral nerve stimuli, delivered at specific inter-stimulus intervals, able to elicit non-invasively long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity in the human motor cortex. PAS has been designed to drive cortical LTP/LTD according to the Hebbian rule of associative plasticity. Over the last two decades, a growing number of researchers have increasingly used the PAS technique to assess cortical associative plasticity in healthy humans and in patients with movement disorders and other neuropsychiatric diseases. The present review covers the physiology, pharmacology, pathology and motor effects of PAS. Further sections of the review focus on new protocols of “modified PAS” and possible future application of PAS in neuromorphic circuits designed for brain-computer interface.

In the recent past, basal ganglia circuitry was simplified as represented by the direct and indirect pathways and by hyperdirect pathways. Based on data from animal studies, we hypothesized a fourth pathway, the cortico-pallidal, pathway, that complements the hyperdirect pathway to the subthalamus. Ten normal brains were analyzed by using the high angular resolution diffusion imaging-constrained spherical deconvolution (CSD)-based technique. The study was performed with a 3T magnetic resonance imaging (MRI) scanner (Achieva, Philips Healthcare, Best, Netherlands); by using a 32-channel SENSE head coil. We showed that CSD is a powerful technique that allows a fine evaluation of both the long and small tracts between cortex and basal ganglia, including direct, indirect, and hyperdirect pathways. In addition, a pathway directly connecting the cortex to the globus pallidus was seen. Our results confirm that the CSD tractography is a valuable technique allowing a reliable reconstruction of small- and long-fiber pathways in brain regions with multiple fiber orientations, such as basal ganglia. This could open a future scenario in which CSD could be used to focally target with deep brain stimulation (DBS) the small bundles within the basal ganglia loops.

Work over the past 2 decades has led to substantial changes in our understanding of dystonia pathophysiology. Three general abnormalities appear to underlie the pathophysiological substrate. The first is a loss of inhibition. This makes sense considering that it may be responsible for the excess of movement and for the overflow phenomena seen in dystonia. A second abnormality is sensory dysfunction which is related to the mild sensory complaints in patients with focal dystonias and may be responsible for some of the motor dysfunction. Third, evidence from animal models of dystonia as well as from patients with primary dystonia has revealed significant alterations of synaptic plasticity characterized by a disruption of homeostatic plasticity, with a prevailing facilitation of synaptic potentiation, together with the loss of synaptic inhibitory processes. We speculate that during motor learning this abnormal plasticity may lead to an abnormal sensorimotor integration, leading to consolidation of abnormal motor engrams. If so, then removing this abnormal plasticity might have little immediate effect on dystonic movements because bad motor memories have already been ''learned'' and are difficult to erase. These considerations might explain the delayed clinical effects of deep brain stimulation (DBS) in patients with generalized dystonia. Current lines of research will be discussed from a network perspective. © 2013 Movement Disorder Society.

This narrative review aims to provide an objective view of the noninvasive neuromodulation (NINM) protocols available for treating spasticity, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). On the basis of the relevant randomized controlled trials, we infer that NINM is more effective in reducing spasticity when combined with the conventional therapies than used as a stand-alone treatment. However, the magnitude of NINM after-effects depends significantly on the applied hemisphere and the underlying pathology. Being in line with these arguments, low-frequency rTMS and cathodal-tDCS over the unaffected hemisphere are more effective in reducing spasticity than high-frequency rTMS and anodal-tDCS over the affected hemisphere in chronic poststroke. However, most of the studies are heterogeneous in the stimulation setup, patient selection, follow-up duration, and the availability of the sham operation. Therefore, the available data on the usefulness of NINM in reducing spasticity need to be confirmed by larger and multicentric randomized controlled trials to gather evidence on the efficiency of NINM regimens in reducing spasticity in various neurologic conditions. Level of Evidence V

Substantia nigra is an important neuronal structure, located in the ventral midbrain, that exerts a regulatory function within the basal ganglia circuitry through the nigro-striatal pathway. Although its subcortical connections are relatively well-known in human brain, little is known about its cortical connections. The existence of a direct cortico-nigral pathway has been demonstrated in rodents and primates but only hypothesized in humans. In this study, we aimed at evaluating cortical connections of substantia nigra in vivo in human brain by using probabilistic constrained spherical deconvolution (CSD) tractography on magnetic resonance diffusion weighted imaging data. We found that substantia nigra is connected with cerebral cortex as a whole, with the most representative connections involving prefrontal cortex, precentral and postcentral gyri and superior parietal lobule. These results may be relevant for the comprehension of the pathophysiology of several neurological disorders involving substantia nigra, such as parkinson's disease, schizophrenia, and pathological addictions.

Neuromodulatory effects of non-invasive brain stimulation (NIBS) have been extensively studied in chronic pain. A hypothetic mechanism of action would be to prevent or revert the ongoing maladaptive plasticity within the pain matrix. In this review, the authors discuss the mechanisms underlying the development of an abnormal plasticity in patients with chronic pain and the putative mechanisms of NIBS in modulating synaptic plasticity in neuropathic pain conditions.

Objectives The inhibition of single nociceptive inputs by single non-painful stimuli was shown to occur at supraspinal level (Testani et al., 2015). However, the neurophysiological mechanism subserving the analgesia induced by rubbing the painful part of the body or during TENS is still unknown. Our aim was to investigate the site of this inhibition. Methods We studied 10 healthy volunteers. LEPs were recorded after stimulation of the radial and ulnar territories of both the right and left hand dorsum in 2 conditions: (1) no conditioning stimulation (baseline condition), and (2) high-frequency (5 Hz) non-painful electrical stimulation of the right radial nerve (gating condition). Results As compared to the baseline, in the gating condition the N2/P2 amplitude was reduced in amplitude after stimulation of the radial territory of both hands ( p 0.001 and p 0.001 for right and left hand, respectively) and of the right ulnar region (p = 0.008), while no inhibition was found to left ulnar region stimulation (p = 0.06). Discussion Our results show that high-frequency non-painful stimulation of the right radial nerve inhibits the nociceptive input coming from both the ispilateral and contralateral homotopic regions, and from a close ispilateral heterotopic territory. On the contrary, it does not have any effect on the nociceptive input due to stimulation of a contralateral heterotopic area. Conclusion Spinal segmental mechanisms are mainly involved in the nociceptive input inhibition by high-frequency non-noxious somatosensory stimulation. Significance Pain inhibition induced by high-frequency somatosensory stimulation, such as TENS, is likely to occur at the spinal cord level.

We tested the hypothesis that fatigue in MS is related to a dysfunction in cortical areas involved in movement preparation. Thirty-three patients with clinically definite MS (16 with fatigue MS-F, 17 without fatigue MS-NF) and a relapsing-remitting course, matched for disease severity and duration, disability scores and level of depression were enrolled. They underwent a combined assessment with magnetic resonance imaging (MRI) and transcranial magnetic stimulation (TMS) and, for the electrophysiological study, were compared with 12 healthy controls. MRI was used to assess regional and total lesion-load volume (LL) on T1- and T2-weighted sequences and total brain volume on T1-weighted sequences. With TMS we tested central motor conduction time, short intracortical inhibition (SICI) and facilitation (ICF), pre-movement facilitation related to a simple reaction time paradigm and the effect of short trains of 5-Hz repetitive TMS (rTMS). No significant differences were found in total and regional LL between MS-F and MS-NF, except for a significant increase in frontal lobe LL in MS-F. Neurophysiological assessment did not disclose any difference of SICI and ICF among the three groups. The significant increase of MEP size produced by 5 Hz rTMS in controls was absent in both MS-NF and MS-F. MS-F lacked pre-movement facilitation compared with MS-NF and controls. The lack of pre-movement facilitation and the increased frontal lobe lesion load were significantly correlated to the FSS score, suggesting that central fatigue in MS is probably due to a dysfunction of cortical motor areas involved in movement preparation.