Transcranial magnetic stimulation of the brain: What is stimulated? - A consensus and critical position paper.

Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field and the stimulated neurons determines axonal depolarization. The induced electric field is influenced by the conductive properties of the tissue compartments and is strongest in the superficial parts of the targeted cortical gyri and underlying white matter. TMS likely targets axons of both excitatory and inhibitory neurons. The propensity of individual axons to fire an action potential in response to TMS depends on their geometry, myelination and spatial relation to the imposed electric field and the physiological state of the neuron. The latter is determined by its transsynaptic dendritic and somatic inputs, intrinsic membrane potential and firing rate. Modeling work suggests that the primary target of TMS is axonal terminals in the crown top and lip regions of cortical gyri. The induced electric field may additionally excite bends of myelinated axons in the juxtacortical white matter below the gyral crown. Neuronal excitation spreads ortho- and antidromically along the stimulated axons and causes secondary excitation of connected neuronal populations within local intracortical microcircuits in the target area. Axonal and transsynaptic spread of excitation also occurs along cortico-cortical and cortico-subcortical connections, impacting on neuronal activity in the targeted network. Both local and remote neural excitation depend critically on the functional state of the stimulated target area and network. TMS also causes substantial direct co-stimulation of the peripheral nervous system. Peripheral co-excitation propagates centrally in auditory and somatosensory networks, but also produces brain responses in other networks subserving multisensory integration, orienting or arousal. The complexity of the response to TMS warrants cautious interpretation of its physiological and behavioural consequences, and a deeper understanding of the mechanistic underpinnings of TMS will be critical for advancing it as a scientific and therapeutic tool.

Depotentiation of associative plasticity is intact in Parkinson's disease with mild dyskinesia.

OBJECTIVE: Depotentiation of homosynaptic plasticity of the primary motor cortex (M1) is impaired in patients with Parkinson's disease (PD) who have developed dyskinesias. In this exploratory study, we tested whether this holds true for heterosynaptic plasticity induced by paired associative stimulation (PAS). METHODS: Dyskinetic (n=11) and Non-dyskinetic (n=11), levodopa-treated PD patients were tested in M1 with PAS25ms alone, PAS25ms preceded by continuous theta-burst stimulation of the cerebellum (cTBSCB-PAS) as a method to evoke a larger plastic response in M1, and each of these two interventions followed by a depotentiation protocol (cTBS150pulses) to M1. RESULTS: PAS25ms and cTBSCB-PAS25ms induced long-term potentiation (LTP)-like responses in both groups of PD patients, with cTBSCB significantly boosting the plastic response. Both these LTP-like responses could be depotentiated by cTBS150, in both groups of patients. CONCLUSIONS: Cerebellar stimulation enhances heterosynaptic plasticity in PD irrespective of dyskinesias. Depotentiation mechanisms of heterosynaptic plasticity are preserved in PD patients, including those with dyskinesias. The lack of depotentiation of LTP-like plasticity as a hallmark of dyskinesia in PD patients is not absolute. The ability to depotentiate LTP-like plasticity may potentially depend on the type of plasticity induced (homosynaptic or heterosynaptic), the circuits involved in these responses and the adequacy of dopaminergic stimulation.

Cerebello-Motor Paired Associative Stimulation and Motor Recovery in Stroke: a Randomized, Sham-Controlled, Double-Blind Pilot Trial.

Cerebellum is a key structure for functional motor recovery after stroke. Enhancing the cerebello-motor pathway by paired associative stimulation (PAS) might improve upper limb function. Here, we conducted a randomized, double-blind, sham-controlled pilot trial investigating the efficacy of a 5-day treatment of cerebello-motor PAS coupled with physiotherapy for promoting upper limb motor function compared to sham stimulation. The secondary objectives were to determine in the active treated group (i) whether improvement of upper limb motor function was associated with changes in corticospinal excitability or changes in functional activity in the primary motor cortex and (ii) whether improvements were correlated to the structural integrity of the input and output pathways. To that purpose, hand dexterity and maximal grip strength were assessed along with TMS recordings and multimodal magnetic resonance imaging, before the first treatment, immediately after the last one and a month later. Twenty-seven patients were analyzed. Cerebello-motor PAS was effective compared to sham in improving hand dexterity (p: 0.04) but not grip strength. This improvement was associated with increased activation in the ipsilesional primary motor cortex (p: 0.04). Moreover, the inter-individual variability in clinical improvement was partly explained by the structural integrity of the afferent (p: 0.06) and efferent pathways (p: 0.02) engaged in this paired associative stimulation (i.e., cortico-spinal and dentato-thalamo-cortical tracts). In conclusion, cerebello-motor-paired associative stimulation combined with physiotherapy might be a promising approach to enhance upper limb motor function after stroke.Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT02284087.

Cerebellum Dysfunction in Patients With PRRT2-Related Paroxysmal Dyskinesia.

BACKGROUND AND OBJECTIVES: The main culprit gene for paroxysmal kinesigenic dyskinesia, characterized by brief and recurrent attacks of involuntary movements, is PRRT2. The location of the primary dysfunction associated with paroxysmal dyskinesia remains a matter of debate and may vary depending on the etiology. While striatal dysfunction has often been implicated in these patients, evidence from preclinical models indicates that the cerebellum could also play a role. We aimed to investigate the role of the cerebellum in the pathogenesis of PRRT2-related dyskinesia in humans. METHODS: We enrolled 22 consecutive right-handed patients with paroxysmal kinesigenic dyskinesia with a pathogenic variant of PRRT2 and their matched controls. Participants underwent a multimodal neuroimaging protocol. We recorded anatomic and diffusion-weighted MRI, as well as resting-state fMRI, during which we tested the aftereffects of sham and repetitive transcranial magnetic stimulation applied to the cerebellum on endogenous brain activity. We quantified the structural integrity of gray matter using voxel-based morphometry, the structural integrity of white matter using fixel-based analysis, and the strength and direction of functional cerebellar connections using spectral dynamic causal modeling. RESULTS: Patients with PRRT2 had decreased gray matter volume in the cerebellar lobule VI and in the medial prefrontal cortex, microstructural alterations of white matter in the cerebellum and along the tracts connecting the cerebellum to the striatum and the cortical motor areas, and dysfunction of cerebellar motor pathways to the striatum and the cortical motor areas, as well as abnormal communication between the associative cerebellum (Crus I) and the medial prefrontal cortex. Cerebellar stimulation modulated communication within the motor and associative cerebellar networks and tended to restore this communication to the level observed in healthy controls. DISCUSSION: Patients with PRRT2-related dyskinesia have converging structural alterations of the motor cerebellum and related pathways with a dysfunction of cerebellar output toward the cerebello-thalamo-striato-cortical network. We hypothesize that abnormal cerebellar output is the primary dysfunction in patients with a PRRT2 pathogenic variant, resulting in striatal dysregulation and paroxysmal dyskinesia. More broadly, striatal dysfunction in paroxysmal dyskinesia might be secondary to aberrant cerebellar output transmitted by thalamic relays in certain disorders. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier: NCT03481491.

Identification of a Brain Network Underlying the Execution of Freely Chosen Movements.

Action selection refers to the decision regarding which action to perform in order to reach a desired goal, that is, the "what" component of intention. Whether the action is freely chosen or externally instructed involves different brain networks during the selection phase, but it is assumed that the way an action is selected should not influence the subsequent execution phase of the same movement. Here, we aim to test this hypothesis by investigating whether the modality of movement selection influences the brain networks involved during the execution phase of the movement. Twenty healthy volunteers performed a delayed response task in an event-related functional magnetic resonance imaging design to compare freely chosen and instructed unimanual or bimanual movements during the execution phase. Using activation analyses, we found that the pre-supplementary motor area (preSMA) and the parietal and cerebellar areas were more activated during the execution phase of freely chosen as compared to instructed movements. Connectivity analysis showed an increase of information flow between the right posterior parietal cortex and the cerebellum for freely chosen compared to instructed movements. We suggest that the parieto-cerebellar network is particularly engaged during freely chosen movement to monitor the congruence between the intentional content of our actions and their outcome.

Plastic responsiveness of motor cortex to paired associative stimulation depends on cerebellar input.

OBJECTIVE: The extent of plastic responses of motor cortex (M1) to paired associative stimulation (PAS) varies among healthy subjects. Continuous theta-burst stimulation (cTBS) of cerebellum enhances the mean PAS-induced plasticity in groups of healthy subjects. We tested whether the initial status of Responder or Non -Responder to PAS, influenced the effect of cerebellar stimulation on PAS-induced plasticity. METHODS: We assessed in 19 young healthy volunteers (8 Responders, 11 Non-Responders to PAS), how cTBS and iTBS (intermittent TBS) applied to the cerebellum before a PAS protocol influenced the plastic responsiveness of M1 to PAS. We tested whether the PAS-induced plastic effects could be depotentiated by a short cTBS protocol applied to M1 shortly after PAS and whether cerebellar stimulation influenced GABA-ergic intracortical inhibition and M1 plasticity in parallel. RESULTS: Cerebellar cTBS restored the M1 response to PAS in Non-Responders while cerebellar iTBS turned the potentiating response to PAS to a depressive response in both groups. The depotentiation protocol abolished both responses. CONCLUSION: Non-Responder status to PAS is a state of M1 amenable to bidirectional plastic modulation when primed by a change in cerebello-thalamic drive. SIGNIFICANCE: The meaning of lack of responsiveness to certain protocols probing plasticity should be reconsidered.

Trans-Spinal Direct Current Stimulation for Managing Primary Orthostatic Tremor.

BACKGROUND: Primary orthostatic tremor (POT) is a rare disorder, characterized by 13 to 18 Hz tremor in the legs when standing and is often refractory to medical treatment. Epidural spinal cord stimulation has been proposed as an alternative treatment. However, this approach is invasive, which limits its application. OBJECTIVE: Trans-spinal direct current stimulation (tsDCS) is a non-invasive method to modulate spinal cord circuits. The aim of this proof-of-concept study was to investigate the potential beneficial effect of tsDCS in POT. METHODS: We conducted a double-blind, sham-controlled study in 16 patients with POT. In two separate visits, patients received sham tsDCS first followed by active (either cathodal or anodal) tsDCS. The primary outcome was the change in time in standing position. Secondary outcomes comprised quantitative assessment of tremor, measurement of corticospinal excitability including short-latency afferent inhibition, and clinical global impression-improvement (CGI-I). Measurements were made at baseline, after sham tsDCS, 0-30 min, and 30-60 min after active conditions. RESULTS: Cathodal-tsDCS reduced tremor amplitude and frequency and lowered corticospinal excitability whereas anodal-tsDCS reduced tremor frequency only. CGI-I scores positively correlated with the time in standing position after both active tsDCS conditions. CONCLUSION: A single session of tsDCS can improve instability in POT. This opens a new vista for experimental treatment options using multiple sessions of spinal DC stimulation. © 2021 International Parkinson and Movement Disorder Society.

Temporal integration of short-duration pulse trains in cochlear implant listeners: Psychophysical and electrophysiological measurements.

While electrically-evoked auditory brainstem response (eABR) thresholds for low-rate pulse trains correlate well with behavioral thresholds measured at the same rate, the correlation is much weaker with behavioral thresholds measured at high rates, such as used clinically. This implies that eABRs to low-rate stimuli cannot be reliably used for objective programming of threshold levels in cochlear implant (CI) users. Here, we investigate whether the use of bunched-up pulses (BUPS), consisting of groups of closely-spaced pulses may be used as an alternative stimulus. Experiment 1 measured psychophysical detection thresholds for several stimuli having a period of 32 ms in nine CI subjects implanted with a Med-EL device. The stimuli differed in the number of pulses present in each period (from 1 to 32), the pulse rate within period (1000 pps and as high as possible for BUPS) and the electrode location (apical or basal). The correlation between psychophysical thresholds obtained for a high-rate (1000 pps) clinical stimulus and for the BUPS stimuli increased as the number of pulses per period of BUPS increased from 1 to 32. This first psychophysical experiment suggests that the temporal processes affecting the threshold of clinical stimuli are also present for BUPS. Experiment 2 measured eABRs on the apical electrode of eight CI subjects for BUPS having 1, 2, 4, 8, 16 or 32 pulses per period. For most subjects, wave V was visible for BUPS having up to 16 pulses per period. The latency of wave V at threshold increased as a function of the number of pulses per period, suggesting that the eABR reflects the integration of multiple pulses at such low levels or that the neural response to each individual pulse increases along the sequence due to facilitation processes. There was also a strong within-subject correlation between electrophysiological and behavioral thresholds for the different BUPS stimuli. This demonstrates that the drop in behavioral threshold obtained when increasing the number of pulses per period of the BUPS can be measured electrophysiologically using eABRs. In contrast, the across-subject correlation between eABR thresholds for BUPS and clinical thresholds remained relatively weak and did not increase with the number of pulses per period. Implications of the use of BUPS for objective programming of CIs are discussed.

Redundancy Among Parameters Describing the Input-Output Relation of Motor Evoked Potentials in Healthy Subjects and Stroke Patients.

Background: Transcranial magnetic stimulation (TMS) is widely used to probe corticospinal excitability through Motor Evoked Potential (MEP) amplitude measurements. The input-output (I/O) curve is a sigmoid-shaped relation between the MEP amplitude at incremented TMS intensities. The aim of this study was to examine the relationships between seven parameters derived from the sigmoid function. Methods: Principal Component Analysis and Spearman's rank correlation matrices were used to determine if the seven I/O curve parameters capture similar or, conversely, different aspects of the corticospinal excitability in 24 healthy subjects and 40 stroke survivors with a hand motor impairment. Results: Maximum amplitude (MEPmax), peak slope, area under the I/O curve (AUC), and MEP amplitude recorded at 140% of the resting motor threshold showed strong linear relationships with each other (ρ > 0.72, p < 0.001). Results were found to be similar in healthy subjects and in both hemispheres of stroke patients. Our results did not support an added benefit of sampling entire I/O curves in both healthy subjects and stroke patients, with the exception of S50, the stimulus intensity needed to obtain half of MEPmax amplitude. Conclusions: This demonstrates that MEP elicited at a single stimulus intensity allows to capture the same characteristics of the corticospinal excitability as measured by the AUC, MEPmax and the peak slope, which may be of interest in both clinical and research settings. However, it is still necessary to plot I/O curves if an effect or a difference is expected at S50.

The supplementary motor area modulates interhemispheric interactions during movement preparation.

The execution of coordinated hand movements requires complex interactions between premotor and primary motor areas in the two hemispheres. The supplementary motor area (SMA) is involved in movement preparation and bimanual coordination. How the SMA controls bimanual coordination remains unclear, although there is evidence suggesting that the SMA could modulate interhemispheric interactions. With a delayed-response task, we investigated interhemispheric interactions underlying normal movement preparation and the role of the SMA in these interactions during the delay period of unimanual or bimanual hand movements. We used functional MRI and transcranial magnetic stimulation in 22 healthy volunteers (HVs), and then in two models of SMA dysfunction: (a) in the same group of HVs after transient disruption of the right SMA proper by continuous transcranial magnetic theta-burst stimulation; (b) in a group of 22 patients with congenital mirror movements (CMM), whose inability to produce asymmetric hand movements is associated with SMA dysfunction. In HVs, interhemispheric connectivity during the delay period was modulated according to whether or not hand coordination was required for the forthcoming movement. In HVs following SMA disruption and in CMM patients, interhemispheric connectivity was modified during the delay period and the interhemispheric inhibition was decreased. Using two models of SMA dysfunction, we showed that the SMA modulates interhemispheric interactions during movement preparation. This unveils a new role for the SMA and highlights its importance in coordinated movement preparation.

Severity of Writer's Cramp is Related to Faulty Motor Preparation.

We characterized, in 37 writer's cramp (WC) patients and 14 healthy volunteers (HV), the buildup of motor representations contralateral ("intended") and ispsilateral ("unintended") to the movement to be produced and the excitability changes in left primary motor cortex during the early reaction time (RT) of a pre-cued reaching movement to pick up a pen with either hand to write. We also tested the excitability of interhemispheric pathways from right dorsal premotor and motor cortices to left motor cortex. During early RT (1) the motor cortex excitability of unintended muscle representations did not decrease in patients as in HV and (2) the connection from the contralateral dorsal premotor cortex to the "intended" motor representation did not function in patients. In HV, the efficiency of intracortical GABA-ergic circuits at rest predicted the degree of excitability changes in the intended motor representation in the early RT. This was not true in patients who had lower efficiency of GABA-ergic circuits. Interestingly, the more severe was the writing impairment, the higher was the level of excitability in the intended and unintended motor representations. It demonstrates, for the first time, that abnormal motor preparation influences the severity of the writing impairment in WC patients.

Global loudness of rising- and falling-intensity tones: How temporal profile characteristics shape overall judgments.

The mechanisms underlying global loudness judgments of rising- or falling-intensity tones were further investigated in two magnitude estimation experiments. By manipulating the temporal characteristics of such stimuli, it was examined whether judgments could be accounted for by an integration of their loudest portion over a certain temporal window associated to a "decay mechanism" downsizing this integration over time for falling ramps. In experiment 1, 1-kHz intensity-ramps were stretched in time between 1 and 16 s keeping their dynamics (difference between maximum and minimum levels) unchanged. While global loudness of rising tones increased up to 6 s, evaluations of falling tones increased at a weaker rate and slightly decayed between 6 and 16 s, resulting in significant differences between the two patterns. In experiment 2, ramps were stretched in time between 2 and 12 s keeping their slopes (rate of change in dB/s) unchanged. In this context, the main effect of duration became non-significant and the interaction between the two profiles remained, although the decay of falling tones was not significant. These results qualitatively support the view that the global loudness computation of intensity-ramps involves an integration of their loudest portions; the presence of a decay mechanism could, however, not be attested.

New insight in spiral drawing analysis methods - Application to action tremor quantification.

OBJECTIVE: Spiral drawing is one of the standard tests used to assess tremor severity for the clinical evaluation of medical treatments. Tremor severity is estimated through visual rating of the drawings by movement disorders experts. Different approaches based on the mathematical signal analysis of the recorded spiral drawings were proposed to replace this rater dependent estimate. The objective of the present study is to propose new numerical methods and to evaluate them in terms of agreement with visual rating and reproducibility. METHODS: Series of spiral drawings of patients with essential tremor were visually rated by a board of experts. In addition to the usual velocity analysis, three new numerical methods were tested and compared, namely static and dynamic unraveling, and empirical mode decomposition. The reproducibility of both visual and numerical ratings was estimated, and their agreement was evaluated. RESULTS: The statistical analysis demonstrated excellent agreement between visual and numerical ratings, and more reproducible results with numerical methods than with visual ratings. CONCLUSIONS: The velocity method and the new numerical methods are in good agreement. Among the latter, static and dynamic unravelling both display a smaller dispersion and are easier for automatic analysis. SIGNIFICANCE: The reliable scores obtained through the proposed numerical methods allow considering that their implementation on a digitized tablet, be it connected with a computer or independent, provides an efficient automatic tool for tremor severity assessment.

Contribution of the supplementary motor area and the cerebellum to the anticipatory postural adjustments and execution phases of human gait initiation.

Several brain structures including the brainstem, the cerebellum and the frontal cortico-basal ganglia network, with the primary and premotor areas have been shown to participate in the functional organization of gait initiation and postural control in humans, but their respective roles remain poorly understood. The aim of this study was to better understand the role of the supplementary motor area (SMA) and posterior cerebellum in the gait initiation process. Gait initiation parameters were recorded in 22 controls both before and after continuous theta burst transcranial stimulation (cTBS) of the SMA and cerebellum, and were compared to sham stimulation, using a randomized double-blind design study. The two phases of gait initiation process were analyzed: anticipatory postural adjustments (APAs) and execution, with recordings of soleus and tibialis anterior muscles. Functional inhibition of the SMA led to a shortened APA phase duration with advanced and increased muscle activity; during execution, it also advanced muscle co-activation and decreased the duration of stance soleus activity. Cerebellar functional inhibition did not influence the APA phase duration and amplitude but increased muscle co-activation, it decreased execution duration and showed a trend to increase velocity, with increased swing soleus muscle duration and activity. The results suggest that the SMA contributes to both the timing and amplitude of the APAs with no influence on step execution and the posterior cerebellum in the coupling between the APAs and execution phases and leg muscle activity pattern during gait initiation.

Anatomical and functional correlates of cortical motor threshold of the dominant hand.

BACKGROUND: Resting Motor threshold (rMT) provides information about cortical motor excitability. Interestingly, the influences of the structural or functional variability of the motor system on the rMT inter-individual variability have been poorly investigated. OBJECTIVE/HYPOTHESIS: To investigate relationships between rMT and measures of brain structures and function of the motor system. The hypothesis is that cortical excitability not only depends on the primary motor cortex (M1) but also on the integration of information originating from its vicinity such as premotor (PMd and SMA) and post-central (S1) cortices. METHODS: We measured brain structures, including grey and white matter properties (cortical volume and fiber coherence respectively), and functional interaction (resting-state functional connectivity-FC) in areas contributing to the corticospinal tract axons, i. e, M1, S1, SMA and PMd in the dominant hemisphere of 21 healthy subjects. RESULTS: The rMT was inversely correlated with the FC between PMd and M1 (r = -0.496, 95%CI: -0.764; -0.081; p = 0.02) and the grey matter volume of the dominant hemisphere (r = -0.463, 95%CI: -0.746; -0.039; p = 0.03). The multiple regression analysis model retained the FC between M1 and PMd (coefficient: -25 ± 9) as well as the grey matter volume of the dominant hemisphere (coefficient: -0.15 ± 0.06) explaining 44% of the variance of the rMT (p: 0.005). When adding age and coil-to-cortex distance, two factors known to influence rMT, the model reached a R2 of 75% (p: 0.0001). CONCLUSIONS: These results underline the major role of the PMd and the cortico-cortical connections toward M1 in the excitation of the corticospinal fibers likely through trans-synaptic pathways.

Non cell-autonomous role of DCC in the guidance of the corticospinal tract at the midline.

DCC, a NETRIN-1 receptor, is considered as a cell-autonomous regulator for midline guidance of many commissural populations in the central nervous system. The corticospinal tract (CST), the principal motor pathway for voluntary movements, crosses the anatomic midline at the pyramidal decussation. CST fails to cross the midline in Kanga mice expressing a truncated DCC protein. Humans with heterozygous DCC mutations have congenital mirror movements (CMM). As CMM has been associated, in some cases, with malformations of the pyramidal decussation, DCC might also be involved in this process in human. Here, we investigated the role of DCC in CST midline crossing both in human and mice. First, we demonstrate by multimodal approaches, that patients with CMM due to DCC mutations have an increased proportion of ipsilateral CST projections. Second, we show that in contrast to Kanga mice, the anatomy of the CST is not altered in mice with a deletion of DCC in the CST. Altogether, these results indicate that DCC controls CST midline crossing in both humans and mice, and that this process is non cell-autonomous in mice. Our data unravel a new level of complexity in the role of DCC in CST guidance at the midline.

Motor cortex plasticity can indicate vulnerability to motor fluctuation and high L-DOPA need in drug-naïve Parkinson's disease.

INTRODUCTION: Motor cortex plasticity is reported to be decreased in Parkinson's disease in studies which pooled patients in various stages of the disease. Whether the early decrease in plasticity is related to the motor signs or is linked to the future development of motor complications of treatment is unclear. The aim of the study was to test if motor cortex plasticity and its cerebellar modulation are impaired in treatment-naïve Parkinson's disease, are related to the motor signs of the disease and predict occurrence of motor complications of treatment. METHODS: Twenty-nine denovo patients with Parkinson's disease were longitudinally assessed for motor complications for four years. Using transcranial magnetic stimulation, the plasticity of the motor cortex and its cerebellar modulation were measured (response to paired-associative stimulation alone or preceded by 2 active cerebellar stimulation protocols), both in the untreated state and after a single dose of L-DOPA. Twenty-six matched, healthy volunteers were tested, only without L-DOPA. RESULTS: Patients and healthy controls had similar proportions of responders and non-responders to plasticity induction. In the untreated state, the more efficient was the cerebellar modulation of motor cortex plasticity, the lower were the bradykinesia and rigidity scores. The extent of the individual plastic response to paired associative stimulation could indicate a vulnerability to develop early motor fluctuation but not dyskinesia. CONCLUSIONS: Measuring motor cortex plasticity in denovo Parkinson's disease could be a neurophysiological parameter that may help identify patients with greater propensity for early motor fluctuations.

Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia.

A role for the cerebellum in causing ataxia, a disorder characterized by uncoordinated movement, is widely accepted. Recent work has suggested that alterations in activity, connectivity, and structure of the cerebellum are also associated with dystonia, a neurological disorder characterized by abnormal and sustained muscle contractions often leading to abnormal maintained postures. In this manuscript, the authors discuss their views on how the cerebellum may play a role in dystonia. The following topics are discussed: The relationships between neuronal/network dysfunctions and motor abnormalities in rodent models of dystonia. Data about brain structure, cerebellar metabolism, cerebellar connections, and noninvasive cerebellar stimulation that support (or not) a role for the cerebellum in human dystonia. Connections between the cerebellum and motor cortical and sub-cortical structures that could support a role for the cerebellum in dystonia. Overall points of consensus include: Neuronal dysfunction originating in the cerebellum can drive dystonic movements in rodent model systems. Imaging and neurophysiological studies in humans suggest that the cerebellum plays a role in the pathophysiology of dystonia, but do not provide conclusive evidence that the cerebellum is the primary or sole neuroanatomical site of origin.

Taking the brakes off the learning curve.

Motor learning is characterized by patterns of cerebello-striato-cortical activations shifting in time, yet the early dynamic and function of these activations remains unclear. Five groups of subjects underwent either continuous or intermittent theta-burst stimulation of one cerebellar hemisphere, or no stimulation just before learning a new motor sequence during fMRI scanning. We identified three phases during initial learning: one rapid, one slow, and one quasi-asymptotic performance phase. These phases were not changed by left cerebellar stimulation. Right cerebellar inhibition, however, accelerated learning and enhanced brain activation in critical motor learning-related areas during the first phase, continuing with reduced brain activation but high-performance in late phase. Right cerebellar excitation did not affect the early learning process, but slowed learning significantly in late phase, along with increased brain activation. We conclude that the right cerebellum is a key factor coordinating other neuronal loops in the early acquisition of an explicit motor sequential skill. Hum Brain Mapp 38:1676-1691, 2017. © 2016 Wiley Periodicals, Inc.