Cerebellar Brain Inhibition Research Articles

No effects of cerebellar transcranial random noise stimulation on cerebellar brain inhibition, visuomotor learning, and pupil diameter.

Cerebellar brain inhibition (CBI) is an inhibitory output from the cerebellum to the primary motor cortex, which is decreased in early motor learning. Transcranial random noise stimulation (tRNS) is a noninvasive brain stimulation to induce brain plastic changes; however, the effects of cerebellar tRNS on CBI and motor learning have not been investigated yet to our knowledge. In this study, whether cerebellar tRNS decreases CBI and improves motor learning was examined, and pupil diameter was measured to examine physiological changes due to the effect of tRNS on motor learning. Thirty-four healthy subjects were assigned to either the cerebellar tRNS group or the Sham group. The subjects performed visuomotor tracking task with ten trials each in the early and late learning stages while receiving the stimulus intervention. CBI and motor evoked potentials were measured before the learning task, after the early learning stage, and after the late learning stage, and pupil diameter was measured during the task. There was no change in CBI in both groups. No group differences in motor learning rates were observed at any learning stages. Pupil diameter was smaller in the late learning stage than in the early learning stage in both groups. The cerebellar tRNS was suggested not to induce changes in CBI and improvement in motor learning, and it did not affect pupil diameter.

The effect of cerebellar TMS on error processing: A combined single-pulse TMS and ERP study

Abstract The present study investigated temporal aspects of cerebellar contributions to the processing of performance errors as indexed by the error-related negativity (ERN) in the response-locked event-related potential (ERP). We co-registered EEG and applied single-pulse transcranial magnetic stimulation (spTMS) to the left posterolateral cerebellum and an extra-cerebellar control region (vertex) while healthy adult volunteers performed a Go/Nogo Flanker Task. In Go trials, TMS pulses were applied at four different time points, with temporal shifts of -100 ms, -50 ms, 0 ms, or +50 ms relative to the individual error latency (IEL, i.e., individual ERN peak latency + median error response time). These stimulation timings were aggregated into early (-100 ms, -50 ms) and late (0 ms, +50 ms) stimulation for the analysis. In Nogo trials, TMS pulses occurred 0 ms, 100 ms, or 300 ms after stimulus onset. Mixed linear model analyses revealed that cerebellar stimulation did not affect error rates overall. No effects were found for response times. As hypothesized, ERN amplitudes were decreased for cerebellar stimulation. No significant differences were found for the error positivity (Pe). Similar to TMS application to probe cerebellar-brain inhibition in the motor domain, the inhibitory tone of the cerebellar cortex may have been disrupted by the pulses. Reduced inhibitory output of the cerebellar cortex may have facilitated the processing of error information for response selection, which is reflected in a decreased ERN.

Theta-tACS modulates cerebellar-related motor functions and cerebellar-cortical connectivity

ObjectiveTo evaluate the effects of cerebellar transcranial alternating current stimulation (tACS) delivered at cerebellar-resonant frequencies, i.e., theta (θ) and gamma (γ), on upper limb motor performance and cerebellum-primary motor cortex (M1) connectivity, as assessed by cerebellar-brain inhibition (CBI), in healthy subjects. MethodsParticipants underwent cerebellar-tACS while performing three cerebellar-dependent motor tasks: (i) rhythmic finger-tapping, (ii) arm reaching-to-grasp (‘grasping’) and (iii) arm reaching-to-point (‘pointing’) an object. Also, we evaluated possible changes in CBI during cerebellar-tACS. Resultsθ-tACS decreased movement regularity during the tapping task and increased the duration of the pointing task compared to sham- and γ-tACS. Additionally, θ-tACS increased the CBI effectiveness (greater inhibition). The effect of θ-tACS on movement rhythm correlated with CBI changes and less tapping regularity corresponded to greater CBI. ConclusionsCerebellar-tACS delivered at the θ frequency modulates cerebellar-related motor behavior and this effect is, at least in part, mediated by changes in the cerebellar inhibitory output onto M1. The effects of θ-tACS may be due to the modulation of cerebellar neurons that resonate to the θ rhythm. SignificanceThese findings contribute to a better understanding of the physiological mechanisms of motor control and provide new evidence on cerebellar non-invasive brain stimulation.

Cerebellar repetitive transcranial magnetic stimulation has no effect on contraction-induced facilitation of corticospinal excitability.

This study aimed to investigate whether the cerebellum contributes to contraction-induced facilitation (CIF) of contralateral corticospinal excitability. To this end, repetitive cerebellar transcranial magnetic stimulation (TMS) was used to test whether it modulates CIF. Overall, 20 healthy young individuals participated in the study. Single-pulse TMS was applied to the left primary motor cortex to induce motor-evoked potentials (MEP) on electromyography of the right first dorsal interosseous (FDI) muscle to test corticospinal excitability. This measurement was conducted during contraction (10% maximum voluntary contraction [MVC]) and rest (0% MVC) of the FDI muscle. CIF, cerebellar brain inhibition (CBI), cortical silent period (cSP), and resting motor threshold (rMT) were measured before and after low-frequency repetitive TMS (crTMS) of the right cerebellum to downregulate cerebellar output. The CIF (contraction/rest of the MEP), CBI (conditioned/unconditioned MEP) during contraction, cSP, and rMT were not affected by crTMS. At rest, CBI was decreased. These findings indicated that the primary motor cortex function for the increase in corticospinal excitability was not affected by crTMS. This study contributes to our understanding of the role of the cerebellum in motor control. Additionally, it may inform decision-making for the site of cerebellar ataxia treatment using non-invasive brain stimulation.

Reflecting the causes of variability of EEG responses elicited by cerebellar TMS

Recently, Fong et al. published EEG responses in cerebral cortex elicited by cerebellar TMS (cbTMS) (Fong et al., 2023), which differ from our recently identified cbTMS-EEG responses (Gassmann et al., 2022). Fong et al. argued that this discrepancy is due to coil placement unsuitable for eliciting cerebellar brain inhibition (CBI) in our study. However, we reliably elicited CBI in our subjects. Consequently, this leads to a compelling discussion on possible reasons for the observed discrepancies in cbTMS-evoked EEG responses. Reliably measuring cbTMS-evoked EEG responses could become an important neurophysiological tool to test effective cerebellum-to-cortex connectivity.

The Effect of taVNS on the Cerebello-Thalamo-Cortical Pathway: a TMS Study

fMRI studies show activation of cerebellum during transcutaneous auricular vagal nerve stimulation (taVNS); however, there is no evidence whether taVNS induced activation of the cerebellum translates to the cerebellar closed loops involved in motor functions. We assessed the propensity of taVNS at 25 Hz (taVNS25) and 100 Hz (taVNS100) to modulate cerebello-thalamo-cortical pathways using transcranial magnetic stimulation. In our double blind within-subjects study thirty-two participants completed one visit during which cerebellar brain inhibition (CBI) was assessed at baseline (no stimulation) and in a randomized order during taVNS100, taVNS25, and sham taVNS (xVNS). Generalized linear mixed models with gamma distribution were built to assess the effect of taVNS on CBI. The estimated marginal means of linear trends during each taVNS condition were computed and compared in a pairwise fashion with Benjamini-Hochberg correction for multiple comparisons. CBI significantly increased during taVNS100 compared to taVNS25 and xVNS (p = 0.0003 and p = 0.0465, respectively). The taVNS current intensity and CBI conditioning stimulus intensity had no significant effect on CBI. taVNS has a frequency dependent propensity to modulate the cerebello-thalamo-cortical pathway. The cerebellum participates in closed-loop circuits involved in motor, cognitive, and affective operations and may serve as an entry for modulating effects of taVNS.

A tablet-based quantitative assessment of manual dexterity for detection of early psychosis.

We performed a pilot study on whether tablet-based measures of manual dexterity can provide behavioral markers for detection of first-episode psychosis (FEP), and whether cortical excitability/inhibition was altered in FEP. Behavioral and neurophysiological testing was undertaken in persons diagnosed with FEP (N = 20), schizophrenia (SCZ, N = 20), autism spectrum disorder (ASD, N = 20), and in healthy control subjects (N = 20). Five tablet tasks assessed different motor and cognitive functions: Finger Recognition for effector (finger) selection and mental rotation, Rhythm Tapping for temporal control, Sequence Tapping for control/memorization of motor sequences, Multi Finger Tapping for finger individuation, and Line Tracking for visuomotor control. Discrimination of FEP (from other groups) based on tablet-based measures was compared to discrimination through clinical neurological soft signs (NSS). Cortical excitability/inhibition, and cerebellar brain inhibition were assessed with transcranial magnetic stimulation. Compared to controls, FEP patients showed slower reaction times and higher errors in Finger Recognition, and more variability in Rhythm Tapping. Variability in Rhythm Tapping showed highest specificity for the identification of FEP patients compared to all other groups (FEP vs. ASD/SCZ/Controls; 75% sensitivity, 90% specificity, AUC = 0.83) compared to clinical NSS (95% sensitivity, 22% specificity, AUC = 0.49). Random Forest analysis confirmed FEP discrimination vs. other groups based on dexterity variables (100% sensitivity, 85% specificity, balanced accuracy = 92%). The FEP group had reduced short-latency intra-cortical inhibition (but similar excitability) compared to controls, SCZ, and ASD. Cerebellar inhibition showed a non-significant tendency to be weaker in FEP. FEP patients show a distinctive pattern of dexterity impairments and weaker cortical inhibition. Easy-to-use tablet-based measures of manual dexterity capture neurological deficits in FEP and are promising markers for detection of FEP in clinical practice.

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

BackgroundConnections 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. ObjectivesWe 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. MethodsIn 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. ResultsA 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. ConclusionsCerebral 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.

Cerebellar Transcranial Direct Current Stimulation Modulates Anticipatory Postural Adjustments in Healthy Adults.

During forward swinging of the arm, the central nervous system must anticipate the effect of upraising upon the body. Little is known about the cerebellar network that coordinates these anticipatory postural adjustments (APAs). Stimulating different cerebellar regions with transcranial direct current stimulation (tDCS) and with different polarities modulated the APAs. We used surface electromyography (sEMG) to measure muscle activities in a bilateral rapid shoulder flexion task. The onset of APAs was altered after tDCS over the vermis, while the postural stability and the kinematics of arm raising were not affected. To our knowledge, this is the first human cerebellar-tDCS (c-tDCS) study to separate cerebellar involvement in core muscle APAs in bilateral rapid shoulder flexion. These data contribute to our understanding of the cerebellar network supporting APAs in healthy adults. Modulated APAs of the erector spinae by tDCS on the vermis may be related to altered cerebellar brain inhibition (CBI), suggesting the importance of the vermal-cerebral connections in APAs regulation.

Investigation of Neuromodulatory Effect of Anodal Cerebellar Transcranial Direct Current Stimulation on the Primary Motor Cortex Using Functional Near-Infrared Spectroscopy.

Cerebellar brain inhibition (CBI), a neural connection between the cerebellum and primary motor cortex (M1), has been researched as a target pathway for neuromodulation to improve clinical outcomes in various neurological diseases. However, conflicting results of anodal cerebellar transcranial direct current stimulation (acb-tDCS) on M1 excitability indicate that additional investigation is required to examine its precise effect. This study aimed to gather evidence of the neuromodulatory effect of acb-tDCS on the M1 using functional near-infrared spectroscopy (fNIRS). Sixteen healthy participants were included in this cross-over study. Participants received real and sham acb-tDCS randomly, with a minimum 1-week washout period between them. The anode and cathode were placed on the right cerebellum and the right buccinator muscle, respectively. Stimulation lasted 20min at an intensity of 2mA, and fNIRS data were recorded for 42min (including a 4-min baseline before stimulation and an 18-min post-stimulation duration) using eight channels attached bilaterally on the M1. acb-tDCS induced a significant decrease in oxyhemoglobin (HbO) concentration (inhibitory effect) in the left (contralateral) M1, whereas it induced a significant increase in HbO concentration (excitatory effect) in the right (ipsilateral) M1 compared to sham tDCS during (p < 0.05) and after stimulation (p < 0.01) in a group level analysis. At the individual level, variations in response to acb-tDCS were observed. Our findings demonstrate the neuromodulatory effects of acb-tDCS on the bilateral M1 in terms of neuronal hemodynamics.

Reduced Cerebellar Brain Inhibition and Vibrotactile Perception in Response to Mechanical Hand Stimulation at Flutter Frequency

The cerebellum is traditionally considered a movement control structure because of its established afferent and efferent anatomical and functional connections with the motor cortex. In the last decade, studies also proposed its involvement in perception, particularly somatosensory acquisition and prediction of the sensory consequences of movement. However, compared to its role in motor control, the cerebellum’s specific role or modulatory influence on other brain areas involved in sensory perception, specifically the primary sensorimotor cortex, is less clear. In the present study, we explored whether peripherally applied vibrotactile stimuli at flutter frequency affect functional cerebello-cortical connections. In 17 healthy volunteers, changes in cerebellar brain inhibition (CBI) and vibration perception threshold (VPT) were measured before and after a 20-min right hand mechanical stimulation at 25 Hz. 5 Hz mechanical stimulation of the right foot served as an active control condition. Performance in a Grooved Pegboard test (GPT) was also measured to assess stimulation’s impact on motor performance. Hand stimulation caused a reduction in CBI (13.16%) and increased VPT but had no specific effect on GPT performance, while foot stimulation had no significant effect on all measures. The result added evidence to the functional connections between the cerebellum and primary motor cortex, as shown by CBI reduction. Meanwhile, the parallel increase in VPT indirectly suggests that the cerebellum influences the processing of vibrotactile stimulus through motor-sensory interactions.

Assessing effective connectivity of the cerebellum with cerebral cortex using TMS-EEG

Background and objectivesThe cerebellum provides important input to the cerebral cortex but its assessment is difficult. Cerebellar brain inhibition tested by paired-coil transcranial magnetic stimulation (TMS) is limited to the motor cortex. Here we sought to measure responses to cerebellar TMS (cbTMS) throughout the cerebral cortex using electroencephalography (EEG). MethodsSingle-pulse TMS was applied with an induced upward current to the right cerebellar hemisphere in 46 healthy volunteers while recording EEG. Multiple control conditions, including TMS of right occipital cortex, cbTMS with induced downward current, and a sham condition modified specifically for cbTMS were tested to provide evidence for the specificity of the EEG responses evoked by cbTMS with an upward induced current. ResultsDistinct EEG response components could be specifically attributed to cbTMS, namely a left-hemispheric prefrontal positive deflection 25 ms after cbTMS, and a subsequent left-hemispheric parietal negative deflection peaking at 45 ms. In the time-frequency-response analysis, cbTMS induced a left-hemispheric prefrontal power increase in the high-beta frequency band. These responses were not seen in the control and sham conditions. ConclusionsThe EEG responses observed in this highly controlled experimental design may cautiously be attributed to reflect specific signatures of the activation of the cerebello-dentato-thalamo-cortical pathway by cbTMS. Therefore, these responses may provide biomarkers for assessing the integrity of this pathway, a proposition that will need further testing in clinical populations.

Cerebellar transcranial current stimulation - An intraindividual comparison of different techniques.

Transcranial current stimulation (tCS) techniques have been shown to induce cortical plasticity. As an important relay in the motor system, the cerebellum is an interesting target for plasticity induction using tCS, aiming to modulate its excitability and connectivity. However, until now it remains unclear, which is the most effective tCS method for inducing plasticity in the cerebellum. Thus, in this study, the effects of anodal transcranial direct current stimulation (tDCS), 50 Hz transcranial alternating current stimulation (50 Hz tACS), and high frequency transcranial random noise stimulation (tRNS) were compared with sham stimulation in 20 healthy subjects in a within-subject design. tCS was applied targeting the cerebellar lobe VIIIA using neuronavigation. We measured corticospinal excitability, short-interval intracortical inhibition (SICI), short-latency afferent inhibition (SAI), and cerebellar brain inhibition (CBI) and performed a sensor-based movement analysis at baseline and three times after the intervention (post1 = 15 min; post2 = 55 min; post3 = 95 min). Corticospinal excitability increased following cerebellar tACS and tRNS compared to sham stimulation. This effect was most pronounced directly after stimulation but lasted for at least 55 min after tACS. Cortico-cortical and cerebello-cortical conditioning protocols, as well as sensor-based movement analyses, did not change. Our findings suggest that cerebellar 50 Hz tACS is the most effective protocol to change corticospinal excitability.

Changes in Corticospinal Excitability and Motor Control During Cerebellar Transcranial Direct Current Stimulation in Healthy Individuals.

Cerebellar transcranial direct current stimulation (ctDCS) modulates the primary motor cortex (M1) via cerebellar brain inhibition (CBI), which affects motor control in humans. However, the effects of ctDCS on motor control are inconsistent because of an incomplete understanding of the real-time changes in the M1 excitability that occur during ctDCS, which determines motor output under regulation by the cerebellum. This study investigated changes in corticospinal excitability and motor control during ctDCS in healthy individuals. In total, 37 healthy individuals participated in three separate experiments. ctDCS (2mA) was applied to the cerebellar hemisphere during the rest condition or a pinch force-tracking task. Motor-evoked potential (MEP) amplitude and the F-wave were assessed before, during, and after ctDCS, and pinch force control was assessed before and during ctDCS. The MEP amplitudes were significantly decreased during anodal ctDCS from 13min after the onset of stimulation, whereas the F-wave was not changed. No significant changes in MEP amplitudes were observed during cathodal and sham ctDCS conditions. The MEP amplitudes were decreased during anodal ctDCS when combined with the pinch force-tracking task, and pinch force control was impaired during anodal ctDCS relative to sham ctDCS. The MEP amplitudes were not significantly changed before and after all ctDCS conditions. Motor cortical excitability was suppressed during anodal ctDCS, and motor control was unskilled during anodal ctDCS when combined with a motor task in healthy individuals. Our findings provided a basic understanding of the clinical application of ctDCS to neurorehabilitation.

Non-invasive electrical stimulation in patients with neurodegenerative ataxia and spasticity: A systematic review and meta-analysis of randomized controlled trials.

There are limited treatment options for patients with neurodegenerative ataxia and spasticity. Non-invasive electrostimulation (NES) is receiving increasing interest because of its ease of implementation, cost-effectiveness and safety. A meta-analysis was conducted to evaluate the efficacy of NES. MEDLINE and Embase were screened for studies using NES in ataxias and spasticity. Key outcome measurements of effectiveness included changes in (1) Modified Ashworth Scale (MAS) scores, (2) cerebellar brain inhibition (CBI), (3) the nine-hole peg test (9HPT), (4) the 8-m walking time (8MWT), (5) International Cooperative Ataxia Rating Scale (ICARS) score and (6) the Scale for Assessment and Rating of Ataxia (SARA) scores. Seven randomized controlled trials involving 203 patients were included. There were significant improvements in MAS (mean difference [MD] -0.42, 95% confidence interval [CI] -0.76 to -0.08, p=0.015), CBI (MD -0.35%, 95% CI -0.42 to -0.28, p < 0.001), 8MWT (MD -1.88 s, 95% CI -3.26 to -0.49, p=0.008), ICARS (MD -7.84, 95% CI -11.90 to -3.78, p < 0.001) and SARA (MD -3.01, 95% CI -4.74 to -1.28, p < 0.001). There was almost no heterogeneity across all outcomes except for CBI (I2 = 79%). No significant changes in the 9HPT were observed comparing NES to a sham procedure (MD -3.52 s, 95% CI -9.15 to 2.10, p=0.220). Most included studies were at low risk of bias, and no severe adverse effects were reported. It was demonstrated that NES is an effective treatment for improving coordination and balance and increased exercise capacity in patients with ataxia and spasticity. There was also a significant modulation of CBI in ataxic patients.

Utilising TMS-EEG to Assess the Response to Cerebellar-Brain Inhibition

Cerebellar-brain inhibition (CBI) is a transcranial magnetic stimulation (TMS) paradigm indexing excitability of cerebellar projections to motor cortex (M1). Stimulation involved with CBI is often considered to be uncomfortable, and alternative ways to index connectivity between cerebellum and the cortex would be valuable. We therefore sought to assess the utility of electroencephalography in conjunction with TMS (combined TMS-EEG) to record the response to CBI. A total of 33 volunteers (25.7 ± 4.9 years, 20 females) participated across three experiments. These investigated EEG responses to CBI induced with a figure-of-eight (F8; experiment 1) or double cone (DC; experiment 2) conditioning coil over cerebellum, in addition to multisensory sham stimulation (experiment 3). Both F8 and DC coils suppressed early TMS-evoked EEG potentials (TEPs) produced by TMS to M1 (P < 0.05). Furthermore, the TEP produced by CBI stimulation was related to the motor inhibitory response to CBI recorded in a hand muscle (P < 0.05), but only when using the DC coil. Multisensory sham stimulation failed to modify the M1 TEP. Cerebellar conditioning produced changes in the M1 TEP that were not apparent following sham stimulation, and that were related to the motor inhibitory effects of CBI. Our findings therefore suggest that it is possible to index the response to CBI using TMS-EEG. In addition, while both F8 and DC coils appear to recruit cerebellar projections, the nature of these may be different.

Role of Cerebellum in the Treatment of Dystonia and Application of Cerebellum Transcranial Magnetic Stimulation

Dystonia is a specific type of abnormal movement characterized by involuntary movement, abnormal posture, or both due to persistent or intermittent muscle contractions. At present, symptomatic treatment is mainly used including a combination of psychological and rehabilitation treatments, oral medications, botulinum toxin injections and deep brain stimulation surgery. Existing animal studies suggested that the cerebellum affects dystonia through at least three mechanisms: 1) abnormal cerebellar efferent signal patterns; 2) abnormal connections between the cerebellum and basal ganglia nuclei; 3) abnormalities in the shape or structure of cerebellar cells. The specific role of cerebellum in dystonia has been explored from clinical and pathological observations, neuroelectrophysiology and neuroimaging. In the past, the main function of cerebellum was to maintain body balance and coordinate movement, while dystonia was mainly a disorder of basal ganglia. In recent years, with the development of the "cerebellum-thalamus-cerebral cortex" circuit, the cerebellum has been considered as a new node related to dystonia. As the role of cerebellum in dystonia becomes more and more important and non-invasive brain stimulation techniques have been developed, repetitive transcranial magnetic stimulation (rTMS) for cerebellum is gradually being used. Transcranial magnetic stimulation (TMS) is one of the most widely used neurophysiological techniques in human research. A magnetic field of varying intensity is applied to the central nervous system to generate local currents in the cerebral cortex. rTMS is the traditional mode of stimulation for TMS. Low frequency magnetic stimulation (≤1 Hz) inhibits cortical excitability in the stimulating region, while high frequency stimulation (&gt;1 Hz) increases the excitability of cortical area of stimulation. Theta rhythm burst stimulation (θ rhythm burst stimulation, TBS) is a new type of rTMS. Intermittent TBS (iTBS) can increase excitability of thecortical area, while continuous TBS (cTBS) can inhibit activation of the cerebral cortex. Based on the theory of cerebellar-brain inhibition, TMS can improve symptoms by modulating cerebellar-brain inhibition. Stimulation of the cerebellar cortex by iTBS can inhibit the development of subsequent associative plasticity in the motor cortex, whereas inhibition of the cerebellar cortex by cTBS can enhance subsequent plasticity in the motor cortex. Therefore, cerebellum has gradually become a new regulatory target of higher brain functional stimulation.

Mental practice modulates functional connectivity between the cerebellum and the primary motor cortex

SummaryOur brain has the extraordinary capacity to improve motor skills through mental practice. Conceptually, this ability is attributed to internal forward models, which are cerebellar neural networks that can predict the sensory consequences of motor commands. In our study, we employed single and dual-coil transcranial magnetic stimulations to probe the level of corticospinal excitability and cerebellar-brain inhibition, respectively, before and after a mental practice session or a control session. Motor skill (i.e., accuracy and speed) was measured using a sequential finger tapping-task. We found that mental practice enhanced both speed and accuracy. In parallel, the functional connectivity between the cerebellum and the primary motor cortex changed, with less inhibition from the first to the second. These findings reveal the existence of neuroplastic changes within the cerebellum, supporting the involvement of internal models after mental practice.

Cerebellar Transcranial Direct Current Stimulation in Spinocerebellar Ataxia Type 3: a Randomized, Double-Blind, Sham-Controlled Trial

Repeated sessions of cerebellar anodal transcranial direct current stimulation (tDCS) have been suggested to modulate cerebellar-motor cortex (M1) connectivity and decrease ataxia severity. However, therapeutic trials involving etiologically homogeneous groups of ataxia patients are lacking. The objective of this study was to investigate if a two-week regimen of daily cerebellar tDCS sessions diminishes ataxia and non-motor symptom severity and alters cerebellar-M1 connectivity in individuals with spinocerebellar ataxia type 3 (SCA3). We conducted a randomized, double-blind, sham-controlled trial in which twenty mildly to moderately affected SCA3 patients received ten sessions of real or sham cerebellar tDCS (i.e., five days per week for two consecutive weeks). Effects were evaluated after two weeks, three months, six months, and twelve months. Change in Scale for the Assessment and Rating of Ataxia (SARA) score after two weeks was defined as the primary endpoint. Static posturography, SCA Functional Index tests, various patient-reported outcome measures, the cerebellar cognitive affective syndrome scale, and paired-pulse transcranial magnetic stimulation to examine cerebellar brain inhibition (CBI) served as secondary endpoints. Absolute change in SARA score did not differ between both trial arms at any of the time points. We observed significant short-term improvements in several motor, cognitive, and patient-reported outcomes after the last stimulation session in both groups but no treatment effects in favor of real tDCS. Nonetheless, some of the patients in the intervention arm showed a sustained reduction in SARA score lasting six or even twelve months, indicating interindividual variability in treatment response. CBI, which reflects the functional integrity of the cerebellothalamocortical tract, remained unchanged after ten tDCS sessions. Albeit exploratory, there was some indication for between-group differences in SARA speech score after six and twelve months and in the number of extracerebellar signs after three and six months. Taken together, our study does not provide evidence that a two-week treatment with daily cerebellar tDCS sessions reduces ataxia severity or restores cerebellar-M1 connectivity in early-to-middle-stage SCA3 patients at the group level. In order to potentially increase therapeutic efficacy, further research is warranted to identify individual predictors of symptomatic improvement.

P 58 EEG responses from direct cerebellar activation with Transcranial Magnetic Stimulation

Introduction: Measuring cortical responses from cerebellar stimulation might provide diagnostic biomarkers for the dentato-thalamo-cortical pathway's integrity. Recent studies have investigated the feasibility of delivering cerebellar stimulation through transcranial magnetic stimulation-electroencephalography (TMS-EEG). TMS-EEG presents several potential advantages and could provide more information than previous methods, which rely on motor output measures. However, past TMS-EEG studies were subject to considerable limitations, including contamination of the TMS-evoked potentials by peripherally-evoked potentials (PEPs). Therefore, we aimed to investigate cortical signatures of cerebellar stimulation, while controlling for confounding factors. Methods: We recruited 23 healthy, right-handed volunteers (13 females, mean ± SD age, 22.4±2.2 years). For each, resting motor threshold was used to titrate the intensity necessary to elicit a detectable cerebellar brain inhibition, which was set as the cerebellar TMS-intensity. A total of 280 single TMS pulses were then delivered to the cerebellum, 140 corresponding to REAL and 140 to SHAM condition. SHAM consisted of TMS to the right shoulder, whereas REAL consisted of both TMS to the right cerebellar hemisphere and to the right shoulder. Two further conditions were tested: TMS to the right occipital cortex and TMS to the right trapezius muscle, with otherwise the same parameters of the REAL condition. These conditions aimed to control for confounding factors, respectively collateral occipital cortex activation and PEPs from cerebellar TMS stimulation. EEG-signals of the different conditions were compared with respect to the evoked responses and changes in the time-frequency response via cluster-based t-tests. Results: Comparison of REAL and SHAM revealed significant differences. While some of these differences were explained by the occipital control stimulation, a left-hemispheric prefrontal early positive deflection at 20-26 ms and a left-hemispheric temporal negative deflection peaking at 45 ms (i.e. both contralateral to the cerebellar stimulation) were specific to the cerebellar stimulation. Furthermore, increased frontal theta power immediately after the TMS pulse was specific to the cerebellar stimulation. Conclusions: The investigation of multiple control conditions allowed for unmasking the cortical response resulting specifically from cerebellar TMS. The observed left-hemispheric prefrontal and subsequent temporal cortex responses were only present in conditions involving cerebellar stimulation and could neither be explained by collateral occipital stimulation, nor by a non-specific somatosensory input. These results are anatomically plausible, as targets of the dentato-thalamo-cortical pathway predominantly involve the contralateral prefrontal cortex and structural connectivity between the cerebellum and the contralateral superior temporal sulcus could be demonstrated in past studies.