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.

Amelioration of Focal Hand Dystonia via Low-Frequency Repetitive Somatosensory Stimulation.

BACKGROUND: Dystonia presents a growing concern based on evolving prevalence insights. Previous research found that, in cervical dystonia, high-frequency repetitive somatosensory stimulation (RSS; HF-RSS) applied on digital nerves paradoxically diminishes sensorimotor inhibitory mechanisms, whereas low-frequency RSS (LF-RSS) increases them. However, direct testing on affected body parts was not conducted. OBJECTIVE: This study aims to investigate whether RSS applied directly to forearm muscles involved in focal hand dystonia can modulate cortical inhibitory mechanisms and clinical symptoms. METHODS: We applied HF-RSS and LF-RSS, the latter either synchronously or asynchronously, on forearm muscles involved in dystonia. Outcome measures included paired-pulse somatosensory evoked potentials, spatial lateral inhibition measured by double-pulse somatosensory evoked potentials, short intracortical inhibition tested with transcranial magnetic stimulation, electromyographic activity from dystonic muscles, and behavioral measures of hand function. RESULTS: Both synchronous and asynchronous low-frequency somatosensory stimulation improved cortical inhibitory interactions, indicated by increased short intracortical inhibition and lateral spatial inhibition, as well as decreased amplitude of paired-pulse somatosensory evoked potentials. Opposite effects were observed with high-frequency stimulation. Changes in electrophysiological markers were paralleled by behavioral outcomes: although low-frequency stimulations improved hand function tests and reduced activation of dystonic muscles, high-frequency stimulation operated in an opposite direction. CONCLUSIONS: Our findings confirm the presence of abnormal homeostatic plasticity in response to RSS in the sensorimotor system of patients with dystonia, specifically in inhibitory circuits. Importantly, this aberrant response can be harnessed for therapeutic purposes through the application of low-frequency electrical stimulation directly over dystonic muscles. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Frequency-Selective Suppression of Essential Tremor via Transcutaneous Spinal Cord Stimulation.

BACKGROUND: Essential tremor (ET) is a common debilitating condition, yet current treatments often fail to provide satisfactory relief. Transcutaneous spinal cord electrical stimulation (tSCS) has emerged as a potential noninvasive neuromodulation technique capable of disrupting the oscillatory activity underlying tremors. OBJECTIVE: This study aimed to investigate the potential of tSCS to disrupt tremor in a frequency-dependent manner in a cohort of patients with ET. METHODS: Eighteen patients with ET completed the study. The experiment consisted of 60-s postural tremor recording, during tSCS at tremor frequency, at 1 Hz, at 21 Hz, no stimulation, and trapezius stimulation. Tremor frequency and amplitude were analyzed and compared across the conditions. RESULTS: We found tremor amplitude reduction at tremor frequency stimulation significant only during the second half of the stimulation. The same stimulation resulted in the highest number of responders. tSCS at 1 Hz showed a trend toward decreased tremor amplitude in the latter half of stimulation. tSCS at 21 Hz did not produce any significant alterations in tremor, whereas trapezius stimulation exacerbated it. Notably, during tremor frequency stimulation, a subgroup of responders exhibited consistent synchronization between tremor phase and delivered stimulation, indicating tremor entrainment. CONCLUSIONS: Cervical tSCS holds promise for alleviating postural tremor in patients with ET when delivered at the subject's tremor frequency. The observed changes in tremor amplitude likely result from the modulation of spinal cord circuits by tSCS, which disrupts the oscillatory drive to muscles by affecting afferent pathways or spinal reflexes. However, the possibility of an interplay between spinal and supraspinal centers cannot be discounted. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Rigidity in Parkinson's disease: evidence from biomechanical and neurophysiological measures.

Although rigidity is a cardinal motor sign in patients with Parkinson's disease (PD), the instrumental measurement of this clinical phenomenon is largely lacking, and its pathophysiological underpinning remains still unclear. Further advances in the field would require innovative methodological approaches able to measure parkinsonian rigidity objectively, discriminate the different biomechanical sources of muscle tone (neural or visco-elastic components), and finally clarify the contribution to 'objective rigidity' exerted by neurophysiological responses, which have previously been associated with this clinical sign (i.e. the long-latency stretch-induced reflex). Twenty patients with PD (67.3 ± 6.9 years) and 25 age- and sex-matched controls (66.9 ± 7.4 years) were recruited. Rigidity was measured clinically and through a robotic device. Participants underwent robot-assisted wrist extensions at seven different angular velocities randomly applied, when ON therapy. For each value of angular velocity, several biomechanical (i.e. elastic, viscous and neural components) and neurophysiological measures (i.e. short and long-latency reflex and shortening reaction) were synchronously assessed and correlated with the clinical score of rigidity (i.e. Unified Parkinson's Disease Rating Scale-part III, subitems for the upper limb). The biomechanical investigation allowed us to measure 'objective rigidity' in PD and estimate the neuronal source of this phenomenon. In patients, 'objective rigidity' progressively increased along with the rise of angular velocities during robot-assisted wrist extensions. The neurophysiological examination disclosed increased long-latency reflexes, but not short-latency reflexes nor shortening reaction, in PD compared with control subjects. Long-latency reflexes progressively increased according to angular velocities only in patients with PD. Lastly, specific biomechanical and neurophysiological abnormalities correlated with the clinical score of rigidity. 'Objective rigidity' in PD correlates with velocity-dependent abnormal neuronal activity. The observations overall (i.e. the velocity-dependent feature of biomechanical and neurophysiological measures of objective rigidity) would point to a putative subcortical network responsible for 'objective rigidity' in PD, which requires further investigation.

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.

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.

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.

A Novel Paired Somatosensory-Cerebellar Stimulation Induces Plasticity on Cerebellar-Brain Connectivity.

The cerebellum receives and integrates a large amount of sensory information that is important for motor coordination and learning. The aim of the present work was to investigate whether peripheral nerve and cerebellum paired associative stimulation (cPAS) could induce plasticity in both the cerebellum and the cortex. In a cross-over design, we delivered right median nerve electrical stimulation 25 or 10 ms before applying transcranial magnetic stimulation over the cerebellum. We assessed changes in motor evoked potentials (MEP), somatosensory evoked potentials (SEP), short-afferent inhibition (SAI), and cerebellum-brain inhibition (CBI) immediately, and 30 min after cPAS. Our results showed a significant reduction in CBI 30 minutes after cPAS, with no discernible changes in MEP, SEP, and SAI. Notably, cPAS10 did not produce any modulatory effects on these parameters. In summary, cPAS25 demonstrated the capacity to induce plasticity effects in the cerebellar cortex, leading to a reduction in CBI. This novel intervention may be used to modulate plasticity mechanisms and motor learning in healthy individuals and patients with neurological conditions.

Short- and long-interval intracortical inhibition in EPM1 is related to genotype.

OBJECTIVE: Progressive myoclonic epilepsy type 1 (EPM1) is caused by biallelic alterations in the CSTB gene, most commonly dodecamer repeat expansions. Although transcranial magnetic stimulation (TMS)-induced long-interval intracortical inhibition (LICI) was previously reported to be normal in EPM1, short-interval intracortical inhibition (SICI) was reduced. We explored the association between these measures and the clinical and genetic features in a separate group of patients with EPM1. METHODS: TMS combined with electromyography was performed under neuronavigation. LICI was induced with an inter-stimulus interval (ISI) of 100 ms, and SICI with ISIs of 2 and 3 ms, and their means (mSICIs) were expressed as the ratio of conditioned to unconditioned stimuli. LICI and mSICI were compared between patients and controls. Nonparametric correlation was used to study the association between inhibition and parameters of clinical severity, including the Unified Myoclonus Rating Scale (UMRS); among patients with EPM1 due to biallelic expansion repeats, also the association with the number of repeats was assessed. RESULTS: The study protocol was completed in 19 patients (15 with biallelic expansion repeats and 4 compound heterozygotes), and 7 healthy, age- and sex-matched control participants. Compared to controls, patients demonstrated significantly less SICI (median mSICI ratio 1.18 vs 0.38; p < .001). Neither LICI nor SICI was associated with parameters of clinical severity. In participants with biallelic repeat expansions, the number of repeats in the more affected allele (greater repeat number [GRN]) correlated with LICI (rho = 0.872; p < .001) and SICI (rho = 0.689; p = .006). SIGNIFICANCE: Our results strengthen the finding of deranged γ-aminobutyric acid (GABA)ergic inhibition in EPM1. LICI and SICI may have use as markers of GABAergic impairment in future trials of disease-modifying treatment in this condition. Whether a higher number of expansion repeats leads to greater GABAergic impairment warrants further study.

Is it possible to compare inhibitory and excitatory intracortical circuits in face and hand primary motor cortex?

Face muscles are important in a variety of different functions, such as feeding, speech and communication of non-verbal affective states, which require quite different patterns of activity from those of a typical hand muscle. We ask whether there are differences in their neurophysiological control that might reflect this. Fifteen healthy individuals were studied. Standard single- and paired-pulse transcranial magnetic stimulation (TMS) methods were used to compare intracortical inhibitory (short interval intracortical inhibition (SICI); cortical silent period (CSP)) and excitatory circuitries (short interval intracortical facilitation (SICF)) in two typical muscles, the depressor anguli oris (DAO), a face muscle, and the first dorsal interosseous (FDI), a hand muscle. TMS threshold was higher in DAO than in FDI. Over a range of intensities, resting SICF was not different between DAO and FDI, while during muscle activation SICF was stronger in FDI than in DAO (P = 0.012). At rest, SICI was stronger in FDI than in DAO (P = 0.038) but during muscle contraction, SICI was weaker in FDI than in DAO (P = 0.034). We argue that although many of the difference in response to the TMS protocols could result from the difference in thresholds, some, such as the reduction of resting SICI in DAO, may reflect fundamental differences in the physiology of the two muscle groups. KEY POINTS: Transcranial magnetic stimulation (TMS) single- and paired-pulse protocols were used to investigate and compare the activity of facilitatory and inhibitory intracortical circuits in a face (depressor anguli oris; DAO) and hand (first dorsal interosseous; FDI) muscles. Several TMS intensities and interstimulus intervals were tested with the target muscles at rest and when voluntarily activated. At rest, intracortical inhibitory activity was stronger in FDI than in DAO. In contrast, during muscle contraction inhibitory activity was stronger in DAO than in FDI. As many previous reports have found, the motor evoked potential threshold was higher in DAO than in FDI. Although many of the differences in response to the TMS protocols could result from the difference in thresholds, some, such as the reduction of resting short interval intracortical inhibition in DAO, may reflect fundamental differences in the physiology of the two muscle groups.

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.

Consensus Paper: Novel Directions and Next Steps of Non-invasive Brain Stimulation of the Cerebellum in Health and Disease.

The cerebellum is involved in multiple closed-loops circuitry which connect the cerebellar modules with the motor cortex, prefrontal, temporal, and parietal cortical areas, and contribute to motor control, cognitive processes, emotional processing, and behavior. Among them, the cerebello-thalamo-cortical pathway represents the anatomical substratum of cerebellum-motor cortex inhibition (CBI). However, the cerebellum is also connected with basal ganglia by disynaptic pathways, and cerebellar involvement in disorders commonly associated with basal ganglia dysfunction (e.g., Parkinson's disease and dystonia) has been suggested. Lately, cerebellar activity has been targeted by non-invasive brain stimulation (NIBS) techniques including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) to indirectly affect and tune dysfunctional circuitry in the brain. Although the results are promising, several questions remain still unsolved. Here, a panel of experts from different specialties (neurophysiology, neurology, neurosurgery, neuropsychology) reviews the current results on cerebellar NIBS with the aim to derive the future steps and directions needed. We discuss the effects of TMS in the field of cerebellar neurophysiology, the potentials of cerebellar tDCS, the role of animal models in cerebellar NIBS applications, and the possible application of cerebellar NIBS in motor learning, stroke recovery, speech and language functions, neuropsychiatric and movement disorders.

Dopamine increases risky choice while D2 blockade shortens decision time.

Dopamine is crucially involved in decision-making and overstimulation within dopaminergic pathways can lead to impulsive behaviour, including a desire to take risks and reduced deliberation before acting. These behavioural changes are side effects of treatment with dopaminergic drugs in Parkinson disease, but their likelihood of occurrence is difficult to predict and may be influenced by the individual's baseline endogenous dopamine state, and indeed correlate with sensation-seeking personality traits. We here collected data on a standard gambling task in healthy volunteers given either placebo, 2.5 mg of the dopamine antagonist haloperidol or 100/25 mg of the dopamine precursor levodopa in a within-subject design. We found an increase in risky choices on levodopa. Choices were, however, made faster on haloperidol with no effect of levodopa on deliberation time. Shortened deliberation times on haloperidol occurred in low sensation-seekers only, suggesting a correlation between sensation-seeking personality trait and baseline dopamine levels. We hypothesise that levodopa increases risk-taking behaviour via overstimulation at both D1 and D2 receptor level, while a single low dose of haloperidol, as previously reported (Frank and O'Reilly 2006), may block D2 receptors pre- and post-synaptically and may paradoxically lead to higher striatal dopamine acting on remaining striatal D1 receptors, causing speedier decision without influencing risk tolerance. These effects could also fit with a recently proposed computational model of the basal ganglia (Moeller and Bogacz 2019; Moeller et al. 2021). Furthermore, our data suggest that the actual dopaminergic drug effect may be dependent on the individual's baseline dopamine state, which may influence our therapeutic decision as clinicians in the future.

Cerebellar-Motor Cortex Connectivity: One or Two Different Networks?

Anterior-posterior (AP) and posterior-anterior (PA) pulses of transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) appear to activate distinct interneuron networks that contribute differently to two varieties of physiological plasticity and motor behaviors (Hamada et al., 2014). The AP network is thought to be more sensitive to online manipulation of cerebellar (CB) activity using transcranial direct current stimulation. Here we probed CB-M1 interactions using cerebellar brain inhibition (CBI) in young healthy female and male individuals. TMS over the cerebellum produced maximal CBI of PA-evoked EMG responses at an interstimulus interval of 5 ms (PA-CBI), whereas the maximum effect on AP responses was at 7 ms (AP-CBI), suggesting that CB-M1 pathways with different conduction times interact with AP and PA networks. In addition, paired associative stimulation using ulnar nerve stimulation and PA TMS pulses over M1, a protocol used in human studies to induce cortical plasticity, reduced PA-CBI but not AP-CBI, indicating that cortical networks process cerebellar inputs in distinct ways. Finally, PA-CBI and AP-CBI were differentially modulated after performing two different types of motor learning tasks that are known to process cerebellar input in different ways. The data presented here are compatible with the idea that applying different TMS currents to the cerebral cortex may reveal cerebellar inputs to both the premotor cortex and M1. Overall, these results suggest that there are two independent CB-M1 networks that contribute uniquely to different motor behaviors.SIGNIFICANCE STATEMENT Connections between the cerebellum and primary motor cortex (M1) are essential for performing daily life activities, as damage to these pathways can result in faulty movements. Therefore, developing and understanding novel approaches to probe this pathway are critical to advancing our understanding of the pathophysiology of diseases involving the cerebellum. Here, we show evidence for two distinct cerebellar-cerebral interactions using cerebellar stimulation in combination with directional transcranial magnetic stimulation (TMS) over M1. These distinct cerebellar-cerebral interactions respond differently to physiological plasticity and to distinct motor learning tasks, which suggests they represent separate cerebellar inputs to the premotor cortex and M1. Overall, we show that directional TMS can probe two distinct cerebellar-cerebral pathways that likely contribute to independent processes of learning.

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.

Examining motor evoked potential amplitude and short-interval intracortical inhibition on the up-going and down-going phases of a transcranial alternating current stimulation (tacs) imposed alpha oscillation.

Many brain regions exhibit rhythmical activity thought to reflect the summed behaviour of large populations of neurons. The endogenous alpha rhythm has been associated with phase-dependent modulation of corticospinal excitability. However, whether exogenous alpha rhythm, induced using transcranial alternating current stimulation (tACS) also has a phase-dependent effect on corticospinal excitability remains unknown. Here, we triggered transcranial magnetic stimuli (TMS) on the up- or down-going phase of a tACS-imposed alpha oscillation and measured motor evoked potential (MEP) amplitude and short-interval intracortical inhibition (SICI). There was no significant difference in MEP amplitude or SICI when TMS was triggered on the up- or down-going phase of the tACS-imposed alpha oscillation. The current study provides no evidence of differences in corticospinal excitability or GABAergic inhibition when targeting the up-going (peak) and down-going (trough) phase of the tACS-imposed oscillation.

Variability of Movement Disorders: The Influence of Sensation, Action, Cognition, and Emotions.

Patients with movement disorders experience fluctuations unrelated to disease progression or treatment. Extrinsic factors that contribute to the variable expression of movement disorders are environment related. They influence the expression of movement disorders through sensory-motor interactions and include somatosensory, visual, and auditory stimuli. Examples of somatosensory effects are stimulus sensitivity of myoclonus on touch and sensory amelioration in dystonia but also some less-appreciated effects on parkinsonian tremor and gait. Changes in visual input may affect practically all types of movement disorders, either by loss of its compensatory role or by disease-related alterations in the pathways subserving visuomotor integration. The interaction between auditory input and motor function is reflected in simple protective reflexes and in complex behaviors such as singing or dancing. Various expressions range from the effect of music on parkinsonian bradykinesia to tics. Changes in body position affect muscle tone and may result in marked fluctuations of rigidity or may affect dystonic manifestations. Factors intrinsic to the patient are related to their voluntary activity and cognitive, motivational, and emotional states. Depending on the situation or disease, they may improve or worsen movement disorders. We discuss various factors that can influence the phenotypic variability of movement disorders, highlighting the potential mechanisms underlying these manifestations. We also describe how motor fluctuations can be provoked during the clinical assessment to help reach the diagnosis and appreciated to understand complaints that seem discrepant with objective findings. We summarize advice and interventions based on the variability of movement disorders that may improve patients' functioning in everyday life. © 2020 International Parkinson and Movement Disorder Society.