Changes in cerebellar output abnormally modulate cortical myoclonus sensorimotor hyperexcitability.

Cortical myoclonus is produced by abnormal neuronal discharges within the sensorimotor cortex, as demonstrated by electrophysiology. Our hypothesis is that the loss of cerebellar inhibitory control over the motor cortex, via cerebello-thalamo-cortical connections, could induce the increased sensorimotor cortical excitability that eventually causes cortical myoclonus. To explore this hypothesis, in the present study we applied anodal transcranial direct current stimulation over the cerebellum of patients affected by cortical myoclonus and healthy controls and assessed its effect on sensorimotor cortex excitability. We expected that anodal cerebellar transcranial direct current stimulation would increase the inhibitory cerebellar drive to the motor cortex and therefore reduce the sensorimotor cortex hyperexcitability observed in cortical myoclonus. Ten patients affected by cortical myoclonus of various aetiology and 10 aged-matched healthy control subjects were included in the study. All participants underwent somatosensory evoked potentials, long-latency reflexes and short-interval intracortical inhibition recording at baseline and immediately after 20 min session of cerebellar anodal transcranial direct current stimulation. In patients, myoclonus was recorded by the means of surface EMG before and after the cerebellar stimulation. Anodal cerebellar transcranial direct current stimulation did not change the above variables in healthy controls, while it significantly increased the amplitude of somatosensory evoked potential cortical components, long-latency reflexes and decreased short-interval intracortical inhibition in patients; alongside, a trend towards worsening of the myoclonus after the cerebellar stimulation was observed. Interestingly, when dividing patients in those with and without giant somatosensory evoked potentials, the increment of the somatosensory evoked potential cortical components was observed mainly in those with giant potentials. Our data showed that anodal cerebellar transcranial direct current stimulation facilitates-and does not inhibit-sensorimotor cortex excitability in cortical myoclonus syndromes. This paradoxical response might be due to an abnormal homeostatic plasticity within the sensorimotor cortex, driven by dysfunctional cerebello-thalamo-cortical input to the motor cortex. We suggest that the cerebellum is implicated in the pathophysiology of cortical myoclonus and that these results could open the way to new forms of treatment or treatment targets.

Feeling of Ownership over an Embodied Avatar's Hand Brings About Fast Changes of Fronto-Parietal Cortical Dynamics.

When we look at our body parts, we are immediately aware that they belong to us and we rarely doubt about the integrity, continuity, and sense of ownership of our body. Despite this certainty, immersive virtual reality (IVR) may lead to a strong feeling of embodiment over an artificial body part seen from a first-person perspective (1PP). Although such feeling of ownership (FO) has been described in different situations, it is not yet understood how this phenomenon is generated at neural level. To track the real-time brain dynamics associated with FO, we delivered transcranial magnetic stimuli over the hand region in the primary motor cortex (M1) and simultaneously recorded electroencephalography (EEG) in 19 healthy volunteers (11 male/8 female) watching IVR renderings of anatomically plausible (full-limb) versus implausible (hand disconnected from the forearm) virtual limbs. Our data show that embodying a virtual hand is temporally associated with a rapid drop of cortical activity of the onlookers' hand region in the M1 contralateral to the observed hand. Spatiotemporal analysis shows that embodying the avatar's hand is also associated with fast changes of activity within an interconnected fronto-parietal circuit ipsilateral to the brain stimulation. Specifically, an immediate reduction of connectivity with the premotor area is paralleled by an enhancement in the connectivity with the posterior parietal cortex (PPC) which is related to the strength of ownership illusion ratings and thus likely reflects conscious feelings of embodiment. Our results suggest that changes of bodily representations are underpinned by a dynamic cross talk within a highly-plastic, fronto-parietal network.SIGNIFICANCE STATEMENT Observing an avatar's body part from a first-person perspective (1PP) induces an illusory embodiment over it. What remains unknown are the cortical dynamics underpinning the embodiment of artificial agents. To shed light on the physiological mechanisms of embodiment we used a novel approach that combines noninvasive stimulation of the cortical motor-hand area and whole-scalp electroencephalographic (EEG) recordings in people observing an embodied artificial limb. We found that just before the illusion started, there is a decrease of activity of the motor-hand area accompanied by an increase of connectivity with the parietal region ipsilateral to the stimulation that reflects the ratings of the embodiment illusion. Our results suggest that changes of bodily representations are underpinned by a dynamic cross talk within a fronto-parietal circuit.

Motor potentials evoked by transcranial magnetic stimulation: interpreting a simple measure of a complex system.

Transcranial magnetic stimulation (TMS) is a non-invasive technique that is increasingly used to study the human brain. One of the principal outcome measures is the motor-evoked potential (MEP) elicited in a muscle following TMS over the primary motor cortex (M1), where it is used to estimate changes in corticospinal excitability. However, multiple elements play a role in MEP generation, so even apparently simple measures such as peak-to-peak amplitude have a complex interpretation. Here, we summarize what is currently known regarding the neural pathways and circuits that contribute to the MEP and discuss the factors that should be considered when interpreting MEP amplitude measured at rest in the context of motor processing and patients with neurological conditions. In the last part of this work, we also discuss how emerging technological approaches can be combined with TMS to improve our understanding of neural substrates that can influence MEPs. Overall, this review aims to highlight the capabilities and limitations of TMS that are important to recognize when attempting to disentangle sources that contribute to the physiological state-related changes in corticomotor excitability.

Standard intensities of transcranial alternating current stimulation over the motor cortex do not entrain corticospinal inputs to motor neurons.

Transcranial alternating current stimulation (TACS) is commonly used to synchronize a cortical area and its outputs to the stimulus waveform, but gathering evidence for this based on brain recordings in humans is challenging. The corticospinal tract transmits beta oscillations (∼21 Hz) from the motor cortex to tonically contracted limb muscles linearly. Therefore, muscle activity may be used to measure the level of beta entrainment in the corticospinal tract due to TACS over the motor cortex. Here, we assessed whether TACS is able to modulate the neural inputs to muscles, which would provide indirect evidence for TACS-driven neural entrainment. In the first part of the study, we ran simulations of motor neuron (MN) pools receiving inputs from corticospinal neurons with different levels of beta entrainment. Results suggest that MNs are highly sensitive to changes in corticospinal beta activity. Then, we ran experiments on healthy human subjects (N = 10) in which TACS (at 1 mA) was delivered over the motor cortex at 21 Hz (beta stimulation), or at 7 Hz or 40 Hz (control conditions) while the abductor digiti minimi or the tibialis anterior muscle were tonically contracted. Muscle activity was measured using high-density electromyography, which allowed us to decompose the activity of pools of motor units innervating the muscles. By analysing motor unit pool activity, we observed that none of the TACS conditions could consistently alter the spectral contents of the common neural inputs received by the muscles. These results suggest that 1 mA TACS over the motor cortex given at beta frequencies does not entrain corticospinal activity. KEY POINTS: Transcranial alternating current stimulation (TACS) is commonly used to entrain the communication between brain regions. It is challenging to find direct evidence supporting TACS-driven neural entrainment due to the technical difficulties in recording brain activity during stimulation. Computational simulations of motor neuron pools receiving common inputs in the beta (∼21 Hz) band indicate that motor neurons are highly sensitive to corticospinal beta entrainment. Motor unit activity from human muscles does not support TACS-driven corticospinal entrainment.

EEG responses induced by cerebellar TMS at rest and during visuomotor adaptation.

BACKGROUND: Connections between the cerebellum and the cortex play a critical role in learning and executing complex behaviours. Dual-coil transcranial magnetic stimulation (TMS) can be used non-invasively to probe connectivity changes between the lateral cerebellum and motor cortex (M1) using the motor evoked potential as an outcome measure (cerebellar-brain inhibition, CBI). However, it gives no information about cerebellar connections to other parts of cortex. OBJECTIVES: We used electroencephalography (EEG) to investigate whether it was possible to detect activity evoked in any areas of cortex by single-pulse TMS of the cerebellum (cerebellar TMS evoked potentials, cbTEPs). A second experiment tested if these responses were influenced by the performance of a cerebellar-dependent motor learning paradigm. METHODS: In the first series of experiments, TMS was applied over either the right or left cerebellar cortex, and scalp EEG was recorded simultaneously. Control conditions that mimicked auditory and somatosensory inputs associated with cerebellar TMS were included to identify responses due to non-cerebellar sensory stimulation. We conducted a follow-up experiment that evaluated whether cbTEPs are behaviourally sensitive by assessing individuals before and after learning a visuomotor reach adaptation task. RESULTS: A TMS pulse over the lateral cerebellum evoked EEG responses that could be distinguished from those caused by auditory and sensory artefacts. Significant positive (P80) and negative peaks (N110) over the contralateral frontal cerebral area were identified with a mirrored scalp distribution after left vs. right cerebellar stimulation. The P80 and N110 peaks were replicated in the cerebellar motor learning experiment and changed amplitude at different stages of learning. The change in amplitude of the P80 peak was associated with the degree of learning that individuals retained following adaptation. Due to overlap with sensory responses, the N110 should be interpreted with caution. CONCLUSIONS: Cerebral potentials evoked by TMS of the lateral cerebellum provide a neurophysiological probe of cerebellar function that complements the existing CBI method. They may provide novel insight into mechanisms of visuomotor adaptation and other cognitive processes.

Reply to: "Reflecting the causes of variability of EEG responses elicited by cerebellar TMS".

In their commentary on our recently published paper about electroencephalographic responses induced by cerebellar transcranial magnetic stimulation (Fong et al., 2023), Gassmann and colleagues (Gassmann et al., 2023b) try to explain the differences between our results and their own previous work on the same topic. We agree with them that many of the differences arise from our use of a different magnetic stimulation coil. However, two unresolved questions remain. (1) Which method is most likely to achieve optimal activation of cerebellar output? (2) To what extent are the evoked cerebellar responses contaminated by concomitant sensory input? We highlight the role of careful experimental design and of combining electrophysiological and behavioural data to obtain reliable TMS-EEG data.

Decreased Frontal Gamma Activity in Alzheimer Disease Patients.

OBJECTIVE: In Alzheimer disease (AD) animal models, synaptic dysfunction has recently been linked to a disorder of high-frequency neuronal activity. In patients, a clear relation between AD and oscillatory activity remains elusive. Here, we attempt to shed light on this relation by using a novel approach combining transcranial magnetic stimulation and electroencephalography (TMS-EEG) to probe oscillatory activity in specific hubs of the frontoparietal network in a sample of 60 mild-to-moderate AD patients. METHODS: Sixty mild-to-moderate AD patients and 21 age-matched healthy volunteers (HVs) underwent 3 TMS-EEG sessions to assess cortical oscillations over the left dorsolateral prefrontal cortex, the precuneus, and the left posterior parietal cortex. To investigate the relations between oscillatory activity, cortical plasticity, and cognitive decline, AD patients underwent a TMS-based neurophysiological characterization and a cognitive evaluation at baseline. The latter was repeated after 24 weeks to monitor clinical evolution. RESULTS: AD patients showed a significant reduction of frontal gamma activity as compared to age-matched HVs. In addition, AD patients with a more prominent decrease of frontal gamma activity showed a stronger impairment of long-term potentiation-like plasticity and a more pronounced cognitive decline at subsequent follow-up evaluation at 24 weeks. INTERPRETATION: Our data provide novel evidence that frontal lobe gamma activity is dampened in AD patients. The current results point to the TMS-EEG approach as a promising technique to measure individual frontal gamma activity in patients with AD. This index could represent a useful biomarker to predict disease progression and to evaluate response to novel pharmacological therapies. ANN NEUROL 2022;92:464-475.

Proactive inhibition is marked by differences in the pattern of motor cortex activity during movement preparation and execution.

Successful human behavior relies on the ability to flexibly alter movements depending on the context in which they are made. One such context-dependent modulation is proactive inhibition, a type of behavioral inhibition used when anticipating the need to stop or change movements. We investigated how the motor cortex might prepare and execute movements made under different contexts. We used transcranial magnetic stimulation (TMS) in different coil orientations [postero-anterior (PA) and antero-posterior (AP) flowing currents] and pulse widths (120 and 30 µs) to probe the excitability of different inputs to corticospinal neurons while participants performed two reaction time tasks: a simple reaction time task and a stop-signal task requiring proactive inhibition. We took inspiration from state space models to assess whether the pattern of motor cortex activity changed due to proactive inhibition (PA and AP neuronal circuits represent the x and y axes of a state space upon which motor cortex activity unfolds during motor preparation and execution). We found that the rise in motor cortex excitability was delayed when proactive inhibition was required. State space visualizations showed altered patterns of motor cortex activity (combined PA120 and AP30 activity) during proactive inhibition, despite adjusting for reaction time. Overall, we show that the pattern of neural activity generated by the motor cortex during movement preparation and execution is dependent upon the context under which the movement is to be made.NEW & NOTEWORTHY Using directional TMS, we find that the human motor cortex flexibly changes its pattern of neural activity depending on the context in which a movement is due to be made. Interestingly, this occurs despite adjusting for reaction time. We also show that state space and dynamical systems models of movement can be noninvasively visualized in humans using TMS, thereby offering a novel method to study these powerful models in humans.

Motor Cortical Network Excitability in Parkinson's Disease.

BACKGROUND: Motor impairment in Parkinson's disease (PD) reflects changes in the basal ganglia-thalamocortical circuit converging on the primary motor cortex (M1) and supplementary motor area (SMA). Previous studies assessed M1 excitability in PD using transcranial magnetic stimulation (TMS)-evoked electromyographic activity. TMS-evoked electroencephalographic activity may unveil broader motor cortical network changes in PD. OBJECTIVE: The aim was to assess motor cortical network excitability in PD. METHODS: We compared TMS-evoked cortical potentials (TEPs) from M1 and the pre-SMA between 20 PD patients tested off and on medication and 19 healthy controls (HCs) and investigated possible correlations with bradykinesia. RESULTS: Off PD patients compared to HCs had smaller P30 responses from the M1s contralateral (M1+) and ipsilateral (M1-) to the most bradykinetic side and increased pre-SMA N40. Dopaminergic therapy normalized the amplitude of M1+ and M1- P30 as well as pre-SMA N40. We found a positive correlation between M1+ P30 amplitude and bradykinesia in off PD patients. CONCLUSIONS: Changes in M1 P30 and pre-SMA N40 in PD suggest that M1 excitability is reduced on both sides, whereas pre-SMA excitability is increased. The effect of dopaminergic therapy and the clinical correlation suggest that these cortical changes may reflect abnormal basal ganglia-thalamocortical activity. TMS electroencephalography provides novel insight into motor cortical network changes related to the pathophysiology of PD. © 2022 International Parkinson and Movement Disorder Society.

A Critical Investigation of Cerebellar Associative Learning in Isolated Dystonia.

BACKGROUND: Impaired eyeblink conditioning is often cited as evidence for cerebellar dysfunction in isolated dystonia yet the results from individual studies are conflicting and underpowered. OBJECTIVE: To systematically examine the influence of dystonia, dystonia subtype, and clinical features over eyeblink conditioning within a statistical model which controlled for the covariates age and sex. METHODS: Original neurophysiological data from all published studies (until 2019) were shared and compared to an age- and sex-matched control group. Two raters blinded to participant identity rescored all recordings (6732 trials). After higher inter-rater agreement was confirmed, mean conditioning per block across raters was entered into a mixed repetitive measures model. RESULTS: Isolated dystonia (P = 0.517) and the subtypes of isolated dystonia (cervical dystonia, DYT-TOR1A, DYT-THAP1, and focal hand dystonia) had similar levels of eyeblink conditioning relative to controls. The presence of tremor did not significantly influence levels of eyeblink conditioning. A large range of eyeblink conditioning behavior was seen in both health and dystonia and sample size estimates are provided for future studies. CONCLUSIONS: The similarity of eyeblink conditioning behavior in dystonia and controls is against a global cerebellar learning deficit in isolated dystonia. Precise mechanisms for how the cerebellum interplays mechanistically with other key neuroanatomical nodes within the dystonic network remains an open research question. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Does epilepsy contribute to the clinical phenotype of C9orf72 mutation in fronto-temporal dementia?

C9orf72 mutation is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. Recently, several reports of patients with FTD who carried the C9orf72 mutation and also manifested epilepsy have been published, since seizures occur in FTD at a higher rate than in the general population, the possible association between epilepsy and C9orf72 mutation remains to be clarified. In the attempt to understand whether epilepsy contributes to the phenotype of the C9orf72 mutation, we compared epilepsy occurrence in patients with FTD who carried the C9orf72 mutation and those who did not. In our sample of 84 patients with FTD, 7.1% of cases reported epilepsy, with no significant differences between subsamples of patients with FTD stratified according to the presence of the C9orf72 mutation or to family history of FTD/parkinsonism/motor neuron disease. Our findings did not support to the possibility that epilepsy represents a characteristic feature of the C9orf72 mutation, as suggested by recent case reports published in the English literature.

Stroke in Patients with Schistosomiasis: Review of Cases in Literature.

Introduction: Cerebral vascular comorbidities may occur in patients with schistosomiasis, as described in case reports. Aim and Methods. We have summarized general clinical and neurological features in patients with stroke associated with schistosomiasis, through a review of case reports in the literature. Investigation Outcomes. A total of eight case reports were retrieved. The mean age of patients was 36.42 ± 16.7 (19 to 56 years), four females, three males, and one anonymous sex. Eosinophilia was the most frequent feature at presentation, followed by cardiac abnormalities, confusion, fever, ataxia, hemiplegia, headache, urticaria, dysphasia, and memory impairment. Patients usually present with watershed infarction or intracranial vasculitis. In one case, extracranial carotid arteries presented with inflammation and stenosis. The patient's serology was positive on admission in five cases. Full neurological recovery was reported in three cases, and partial improvement in another three. In two cases, information on neurological outcomes was incomplete. Stroke in schistosomiasis can be caused by haemodynamic impairment, direct lesion to the arterial wall, vasa vasorum obliterative endarteritis, contiguity with a focus of inflamed tissue, or inflammatory intimal damage. Schistosomiasis needs to be included in the differential diagnosis of stroke in people living or coming back from endemic areas. Conclusions: Further studies addressing the noncommunicable comorbidity issues related to this condition are needed.

Corticospinal excitability modulation by pairing peripheral nerve stimulation with cortical states of movement initiation.

KEY POINTS: We compare the effects on corticospinal excitability of repeatedly delivering peripheral nerve stimulation at three time points (-30 ms, 0 ms, +50 ms) relative to muscle onset in a cue-guided task. Plastic changes in excitability are only observed when stimuli are delivered immediately before the time when muscles activate, while stimuli delivered at muscle onset or shortly later (0, +50 ms) have no effect. Plastic effects are abolished if there is ongoing volitional electromyogram activity in the muscles prior to the onset of the phasic contraction. The plastic effects induced by timing peripheral stimulation relative to electromyographic markers of muscle activation are as effective as those that occur if stimulation is timed relative to electroencephalographic markers of motor cortical activation. We provide a simple alternative protocol to induce plasticity in people in whom electroencephalogram recording is difficult. ABSTRACT: Plastic changes in corticospinal excitability (CSE) and motor function can be induced in a targeted and long-term manner if afferent volleys evoked by peripheral nerve stimulation are repeatedly associated with the peak of premovement brain activity assessed with an electroencephalogram (EEG). The present study investigated whether other factors might also characterize this optimal brain state for plasticity induction. In healthy human volunteers (n = 24), we found that the same reliable changes in CSE can be induced by timing peripheral afferent stimulation relative to the onset of electromyogram (EMG) activity rather than using the EEG peak. Specifically, we observed an increase in CSE when peripheral stimulation activated the cortex just before movement initiation. By contrast, there was no effect on CSE if the afferent input reached the cortex at the same time or after EMG onset, consistent with the idea that the temporal order of synaptic activation from afferent input and voluntary movement is important for production of plasticity. Finally, in 14 volunteers, we found that background voluntary muscle activity prior to movement also abolished the effect on CSE. One possible explanation is that the intervention strengthens synapses that are inactive at rest but change their activity in anticipation of movement, and that the intervention fails when the synapses are tonically active during background EMG activity. Overall, we demonstrate that, in individuals with voluntary control of muscles targeted by our intervention, EMG signals are a suitable alternative to an EEG for inducing plasticity by coupling movement-related brain states with peripheral afferent input.

Evidence for interhemispheric imbalance in stroke patients as revealed by combining transcranial magnetic stimulation and electroencephalography.

Interhemispheric interactions in stroke patients are frequently characterized by abnormalities, in terms of balance and inhibition. Previous results showed an impressive variability, mostly given to the instability of motor-evoked potentials when evoked from the affected hemisphere. We aim to find reliable interhemispheric measures in stroke patients with a not-evocable motor-evoked potential from the affected hemisphere, by combining transcranial magnetic stimulation (TMS) and electroencephalography. Ninteen stroke patients (seven females; 61.26 ± 9.8 years) were studied for 6 months after a first-ever stroke in the middle cerebral artery territory. Patients underwent four evaluations: clinical, cortical, corticospinal, and structural. To test the reliability of our measures, the evaluations were repeated after 3 weeks. To test the sensitivity, 14 age-matched healthy controls were compared to stroke patients. In stroke patients, stimulation of the affected hemisphere did not result in any inhibition onto the unaffected. The stimulation of the unaffected hemisphere revealed a preservation of the inhibition mechanism onto the affected. This resulted in a remarkable interhemispheric imbalance, whereas this mechanism was steadily symmetric in healthy controls. This result was stable when cortical evaluation was repeated after 3 weeks. Importantly, patients with a better recovery of the affected hand strength were the ones with a more stable interhemispheric balance. Finally, we found an association between microstructural integrity of callosal fibers, suppression of interhemispheric TMS-evoked activity and interhemispheric connectivity. We provide direct and sensitive cortical measures of interhemispheric imbalance in stroke patients. These measures offer a reliable means of distinguishing healthy and pathological interhemispheric dynamics.

The Signature of Primary Writing Tremor Is Dystonic.

BACKGROUND: It has been debated for decades whether primary writing tremor is a form of dystonic tremor, a variant of essential tremor, or a separate entity. We wished to test the hypothesis that primary writing tremor and dystonia share a common pathophysiology. OBJECTIVES: The objective of the present study was to investigate the pathophysiological hallmarks of dystonia in patients affected by primary writing tremor. METHODS: Ten patients with idiopathic dystonic tremor syndrome, 7 with primary writing tremor, 10 with essential tremor, and 10 healthy subjects were recruited. They underwent eyeblink classic conditioning, blink recovery cycle, and transcranial magnetic stimulation assessment, including motor-evoked potentials and short- and long-interval intracortical inhibition at baseline. Transcranial magnetic stimulation measures were also recorded after paired-associative plasticity protocol. RESULTS: Primary writing tremor and dystonic tremor syndrome had a similar pattern of electrophysiological abnormalities, consisting of reduced eyeblink classic conditioning learning, reduced blink recovery cycle inhibition, and a lack of effect of paired-associative plasticity on long-interval intracortical inhibition. The latter 2 differ from those obtained in essential tremor and healthy subjects. Although not significant, slightly reduced short-interval intracortical inhibition and a larger effect of paired-associative plasticity in primary writing tremor and dystonic tremor syndrome, compared with essential tremor and healthy subjects, was observed. CONCLUSIONS: Our initial hypothesis of a common pathophysiology between dystonia and primary writing tremor has been confirmed. Primary writing tremor might be considered a form of dystonic tremor. © 2021 International Parkinson and Movement Disorder Society.

Defective Somatosensory Inhibition and Plasticity Are Not Required to Develop Dystonia.

BACKGROUND: Dystonia may have different neuroanatomical substrates and pathophysiology. This is supported by studies on the motor system showing, for instance, that plasticity is abnormal in idiopathic dystonia, but not in dystonia secondary to basal ganglia lesions. OBJECTIVE: The aim of this study was to test whether somatosensory inhibition and plasticity abnormalities reported in patients with idiopathic dystonia also occur in patients with dystonia caused by basal ganglia damage. METHODS: Ten patients with acquired dystonia as a result of basal ganglia lesions and 12 healthy control subjects were recruited. They underwent electrophysiological testing at baseline and after a single 45-minute session of high-frequency repetitive somatosensory stimulation. Electrophysiological testing consisted of somatosensory temporal discrimination, somatosensory-evoked potentials (including measurement of early and late high-frequency oscillations and the spatial inhibition ratio of N20/25 and P14 components), the recovery cycle of paired-pulse somatosensory-evoked potentials, and primary motor cortex short-interval intracortical inhibition. RESULTS: Unlike previous reports of patients with idiopathic dystonia, patients with acquired dystonia did not differ from healthy control subjects in any of the electrophysiological measures either before or after high-frequency repetitive somatosensory stimulation, except for short-interval intracortical inhibition, which was reduced at baseline in patients compared to control subjects. CONCLUSIONS: The data show that reduced somatosensory inhibition and enhanced cortical plasticity are not required for the clinical expression of dystonia, and that the abnormalities reported in idiopathic dystonia are not necessarily linked to basal ganglia damage. © 2020 International Parkinson and Movement Disorder Society.

Reversal of Temporal Discrimination in Cervical Dystonia after Low-Frequency Sensory Stimulation.

BACKGROUND: Somatosensory temporal discrimination is abnormal in dystonia and reflects reduced somatosensory inhibition. In healthy individuals, both the latter are enhanced by high-frequency repetitive somatosensory stimulation, whereas opposite effects are observed in patients with cervical dystonia. OBJECTIVES: We tested whether low-frequency repetitive sensory stimulation, which in healthy individuals worsens discrimination, might have the opposite effect in patients with cervical dystonia at the physiological level and, in turn, improve their perceptual performance. METHODS: Somatosensory temporal discrimination and several electrophysiological measures of sensorimotor inhibition were collected before and after 45 minutes of low-frequency repetitive sensory stimulation. RESULTS: As predicted, and opposite to what happened in controls, low-frequency repetitive sensory stimulation in patients enhanced sensorimotor inhibition and normalized somatosensory temporal discrimination. CONCLUSIONS: Patients with cervical dystonia have an abnormal response to repetitive sensory stimulation, which we hypothesize is attributed to abnormally sensitive homeostatic mechanisms of inhibitory circuitry in both sensory and motor systems. © 2020 International Parkinson and Movement Disorder Society.

Unravelling the enigma of cortical tremor and other forms of cortical myoclonus.

Cortical tremor is a fine rhythmic oscillation involving distal upper limbs, linked to increased sensorimotor cortex excitability, as seen in cortical myoclonus. Cortical tremor is the hallmark feature of autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE), a syndrome not yet officially recognized and characterized by clinical and genetic heterogeneity. Non-coding repeat expansions in different genes have been recently recognized to play an essential role in its pathogenesis. Cortical tremor is considered a rhythmic variant of cortical myoclonus and is part of the 'spectrum of cortical myoclonus', i.e. a wide range of clinical motor phenomena, from reflex myoclonus to myoclonic epilepsy, caused by abnormal sensorimotor cortical discharges. The aim of this update is to provide a detailed analysis of the mechanisms defining cortical tremor, as seen in FCMTE. After reviewing the clinical and genetic features of FCMTE, we discuss the possible mechanisms generating the distinct elements of the cortical myoclonus spectrum, and how cortical tremor fits into it. We propose that the spectrum is due to the evolution from a spatially limited focus of excitability to recruitment of more complex mechanisms capable of sustaining repetitive activity, overcoming inhibitory mechanisms that restrict excitatory bursts, and engaging wide areas of cortex. Finally, we provide evidence for a possible common denominator of the elements of the spectrum, i.e. the cerebellum, and discuss its role in FCMTE, according to recent genetic findings.

Impaired automatic but intact volitional inhibition in primary tic disorders.

The defining character of tics is that they can be transiently suppressed by volitional effort of will, and at a behavioural level this has led to the concept that tics result from a failure of inhibition. However, this logic conflates the mechanism responsible for the production of tics with that used in suppressing them. Volitional inhibition of motor output could be increased to prevent the tic from reaching the threshold for expression, although this has been extensively investigated with conflicting results. Alternatively, automatic inhibition could prevent the initial excitation of the striatal tic focus-a hypothesis we have previously introduced. To reconcile these competing hypotheses, we examined different types of motor inhibition in a group of 19 patients with primary tic disorders and 15 healthy volunteers. We probed proactive and reactive inhibition using the conditional stop-signal task, and applied transcranial magnetic stimulation to the motor cortex, to assess movement preparation and execution. We assessed automatic motor inhibition with the masked priming task. We found that volitional movement preparation, execution and inhibition (proactive and reactive) were not impaired in tic disorders. We speculate that these mechanisms are recruited during volitional tic suppression, and that they prevent expression of the tic by inhibiting the nascent excitation released by the tic generator. In contrast, automatic inhibition was abnormal/impaired in patients with tic disorders. In the masked priming task, positive and negative compatibility effects were found for healthy controls, whereas patients with tics exhibited strong positive compatibility effects, but no negative compatibility effect indicative of impaired automatic inhibition. Patients also made more errors on the masked priming task than healthy control subjects and the types of errors were consistent with impaired automatic inhibition. Errors associated with impaired automatic inhibition were positively correlated with tic severity. We conclude that voluntary movement preparation/generation and volitional inhibition are normal in tic disorders, whereas automatic inhibition is impaired-a deficit that correlated with tic severity and thus may constitute a potential mechanism by which tics are generated.

Qualitative smell/taste disorders as sequelae of acute COVID-19.

BACKGROUND: Qualitative smell/taste disorders (such as phantosmia, parosmia, phantogeusia, and parageusia) have not yet been fully characterized in patients who had COVID-19, whereas quantitative disturbances (i.e., reduction/loss of smell/taste) have been widely investigated. OBJECTIVE: To simultaneously assess the presence of both quantitative and qualitative smell/taste dysfunctions in patients who suffered from COVID-19. METHODS: We enrolled 17 consecutive patients who suffered from COVID-19 over the last 6 months and 21 healthy controls, matched for sex and age. After a negative nasopharyngeal swab, the Sniffin' Sticks Test and the Taste Strips were used to assess olfactory and taste function, respectively. At the same time, the presence of phantosmia, parosmia, phantogeusia, and parageusia was investigated with a standardized questionnaire. RESULTS: Qualitative disturbances of smell and/or taste were found in 6/17 (35.3%) patients. Phantosmia was reported in 2/17 (11.8%) patients and parosmia in 4/17 (23.5%). There were no significant differences in smell test scores between patients who reported phantosmia and/or parosmia and patients who did not. Phantogeusia was described in 3/17 (17.6%) patients, and parageusia was identified in 4/17 (23.5%) patients. All tested patients were normogeusic. CONCLUSION: Around one-third of patients who recover from COVID-19 may have persistent qualitative dysfunction in smell/taste domains. Detection of phantogeusia in long-term COVID-19 patients represents a further novel finding. Further investigation is needed to better characterize the pathophysiology of phantosmia, parosmia, phantogeusia, and parageusia in patients who had COVID-19.