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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 STATEMENTConnections 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.

Alzheimer's disease (AD) is considered the most harmful form of dementia in the elderly population. At present, there are no effective treatments and this is likely due to the incomplete understanding of the pathophysiology. Recent data indicate that synaptic dysfunction could be a central element of AD pathophysiology. It was found that a synaptic breakdown is an early event that heralds neuronal degeneration. Transcranial magnetic stimulation (TMS) has been recently introduced as a novel approach to identify the early signatures of synaptic dysfunction characterizing AD pathophysiology. In this chapter, we review the new neurophysiologic signatures of AD that have been emphasized by TMS studies. We show how TMS measurement of neuroplasticity identified long-term potentiation (LTP)-like cortical plasticity as a key element of AD synaptic dysfunction. These measurements are useful to increase the accuracy of differential diagnosis, predict disease progression, and anticipate response to therapy. Moreover, enhancing neuroplasticity holds as a promising therapeutic approach to improve cognition in AD. In recent years, studies showed treatments with multiple sessions of rTMS can influence cognition in people with neurodegenerative diseases. In the second part of this chapter, we also consider novel therapeutic approaches based on the clinical use of rTMS.

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

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.

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.

Background Short-latency intracortical inhibition (SICI) is extensively used to probe GABAergic inhibitory mechanisms in M1. Task-related changes in SICI are presumed to reflect changes in the central excitability of GABAergic pathways. Usually, the level of SICI is evaluated using a single intensity of conditioning stimulus so that inhibition can be compared in different brain states. Objective Here, we show that this approach may sometimes be inadequate since distinct conclusions can be drawn if a different CS intensity is used. Methods We measured SICI using a range of CS intensities at rest and during a warned simple reaction time task. Conclusions Our results show that SICI changes that occurred during the task could be either larger or smaller than at rest depending on the intensity of the CS. These findings indicate that careful interpretation of results are needed when a single intensity of CS is used to measure task-related physiological changes., Highlights • We measured SICI using several conditioning stimulus (CS) intensities at rest and during a warned simple reaction time task. • Pre-movement SICI changes can be either larger or smaller than at rest depending on the intensity of the CS used. • Careful interpretation of SICI is needed when a single intensity of CS is used to measure task-related physiological changes.

Background Stimulating the cerebellum with transcranial magnetic stimulation is often perceived as uncomfortable. No study has systematically tested which coil design can effectively trigger a cerebellar response with the least discomfort. Objective To determine the relationship between perceived discomfort and effectiveness of cerebellar stimulation using different coils: MagStim (70 mm, 110 mm-coated, 110-uncoated), MagVenture and Deymed. Methods Using the cerebellar-brain inhibition (CBI) protocol, we conducted a CBI recruitment curve with respect to each participant’s maximum tolerated-stimulus intensity (MTI) to assess how effective each coil was at activating the cerebellum. Results Only the Deymed double-cone coil elicited CBI at low intensities (−20% MTI). At the MTI, the MagStim (110 mm coated/uncoated) and Deymed coils produced reliable CBI, whereas no CBI was found with the MagVenture coil. Conclusion s: The Deymed double-cone coil was most effective at cerebellar stimulation at tolerable intensities. These results can guide coil selection and stimulation parameters when designing cerebellar TMS studies.

Background Reward-based feedback given during motor learning has been shown to improve the retention of the behaviour being acquired. Interestingly, applying transcranial direct current stimulation (tDCS) during learning over the primary motor cortex (M1), an area associated with motor retention, also results in enhanced retention of the newly formed motor memories. However, it remains unknown whether combining these distinct interventions result in an additive benefit of motor retention. Methods We investigated whether combining both interventions while participants learned to account for a visuomotor transformation results in enhanced motor retention (total n = 56; each group n = 14). To determine whether these interventions share common physiological mechanisms underpinning learning, we assessed motor cortical excitability and inhibition (i.e. SICI) on a hand muscle before and after all participants learned the visuomotor rotation using their entire arm and hand. Results We found that both the Reward-Stim (i.e. reward + tDCS) and Reward-Sham (i.e. reward-only) groups had increased retention at the beginning of the retention phase, indicating an immediate effect of reward on behaviour. However, each intervention on their own did not enhance retention when compared to sham, but rather, only the combination of both reward and tDCS demonstrated prolonged retention. We also found that only the Reward-Stim group had a significant reduction in SICI after exposure to the perturbation. Conclusions We show that combining both interventions are additive in providing stronger retention of motor adaptation. These results indicate that the reliability and validity of using tDCS within a clinical context may depend on the type of feedback individuals receive when learning a new motor pattern., Highlights • Concurrently administering reward and M1 tDCS during learning results in enhanced motor retention. • The combination of these interventions also leads to a reduction in M1 inhibitory mechanisms. • No benefits of motor retention were found when reward or M1 tDCS were given alone.

Apathy is a behavioral syndrome that has been suggested to share similar neuro-physiological pathways with frailty.To investigate the cross-sectional association between apathy and frailty using original data from dementia-free, community-dwelling older adults.A cross-sectional analysis was performed to test the association between frailty (according to Fried's frailty phenotype) and apathy (defined by three items from Geriatric Depression Scale) using data from MAPT, a 3-year, randomized, multicenter, placebo-controlled trial among community-dwelling, dementia-free participants (1.679 individuals with mean age of 75 years).The ordinal logistic regression showed that apathetic individuals had a two-fold more probability to be rated as frail (OR 2.20, 95% CI 1.7-2.9), when adjusting for confounders. Apathetic individuals display a two-fold more likelihood to be rated as pre-frail (RRR 2.1; 95% CI 1.5-2.8) and a three-fold higher probability to be rated as frail (RRR 3.5, 95% CI 1.8-6.9) compared to robust participants.Although data on the associations between apathy and frailty are scarce, these conditions potentially shares physiological mechanisms and were found to be closely associated. Temporal association between frailty and apathy deserve to be further investigated.

Learning new motor behaviors or adjusting previously learned actions to account for dynamic changes in our environment requires the operation of multiple distinct motor learning processes, which rely on different neuronal substrates. For instance, humans are capable of acquiring new motor patterns via the formation of internal model representations of the movement dynamics and through positive reinforcement. In this review, we will discuss how changes in human physiological markers, assessed with noninvasive brain stimulation techniques from distinct brain regions, can be utilized to provide insights toward the distinct learning processes underlying motor learning. We will summarize the findings from several behavioral and neurophysiological studies that have made efforts to understand how distinct processes contribute to and interact when learning new motor behaviors. In particular, we will extensively review two types of behavioral processes described in human sensorimotor learning: (1) a recalibration process of a previously learned movement and (2) acquiring an entirely new motor control policy, such as learning to play an instrument. The selected studies will demonstrate in-detail how distinct physiological mechanisms contributions change depending on the time course of learning and the type of behaviors being learned.

Acquiring complex motor skills involves learning a number of distinct motor components. Two fundamental elements that constitute a skill are the internal representation (i.e., the calibration of a sensorimotor map) and the sequence of movements needed to execute the task. Learning each of these likely rely on different neural substrates such as the cerebellum and primary motor cortex (M1), and physiological mechanisms. However, the specific neurophysiological processes underlying the acquisition of these components remains poorly understood. Here we used non-invasive brain stimulation to identify distinct physiological contributions arising from the cerebellum and M1 associated with learning the internal representation and the sequence of movements to execute a skill. Experiment one evaluated neurophysiological markers of the cerebellum and M1 while participants learned a sensorimotor map. Participants learned to calibrate the appropriate motor outputs to interact with a new device, prior to learning a new motor skill. We found that plastic changes in the cerebellum, but not in M1, are linked to learning the internal representation. Experiment two assessed the same neurophysiological markers while participants learned a sequence of movements, independent of acquiring a novel sensorimotor map. Here, both M1 LTP-like plasticity and cerebellar plasticity mediated movement sequence learning. Our findings indicate that learning the different components that will constitute a motor skill engages multiple nodes of a brain network in a concerted manner. In addition, it calls into question the expectation that targeting specific brain regions, such as M1, with brain stimulation to augment complex skill learning will have positive results.

One of the functions of the cerebellum in motor learning is to predict and account for systematic changes to the body or environment. This form of adaptive learning is mediated by plastic changes occurring within the cerebellar cortex. The strength of cerebellar-to-cerebral pathways for a given muscle may reflect aspects of cerebellum-dependent motor adaptation. These connections with motor cortex (M1) can be estimated as cerebellar inhibition (CBI): a conditioning pulse of transcranial magnetic stimulation delivered to the cerebellum before a test pulse over motor cortex. Previously, we have demonstrated that changes in CBI for a given muscle representation correlate with learning a motor adaptation task with the involved limb. However, the specificity of these effects is unknown. Here, we investigated whether CBI changes in humans are somatotopy specific and how they relate to motor adaptation. We found that learning a visuomotor rotation task with the right hand changed CBI, not only for the involved first dorsal interosseous of the right hand, but also for an uninvolved right leg muscle, the tibialis anterior, likely related to inter-effector transfer of learning. In two follow-up experiments, we investigated whether the preparation of a simple hand or leg movement would produce a somatotopy-specific modulation of CBI. We found that CBI changes only for the effector involved in the movement. These results indicate that learning-related changes in cerebellar–M1 connectivity reflect a somatotopy-specific interaction. Modulation of this pathway is also present in the context of interlimb transfer of learning.SIGNIFICANCE STATEMENTConnectivity between the cerebellum and motor cortex is a critical pathway for the integrity of everyday movements and understanding the somatotopic specificity of this pathway in the context of motor learning is critical to advancing the efficacy of neurorehabilitation. We found that adaptive learning with the hand affects cerebellar–motor cortex connectivity, not only for the trained hand, but also for an untrained leg muscle, an effect likely related to intereffector transfer of learning. Furthermore, we introduce a novel method to measure cerebellar–motor cortex connectivity during movement preparation. With this technique, we show that, outside the context of learning, modulation of cerebellar–motor cortex connectivity is somatotopically specific to the effector being moved.

Learning motor tasks involves distinct physiological processes in the cerebellum (CB) and primary motor cortex (M1). Previous studies have shown that motor learning results in at least two important neurophysiological changes: modulation of cerebellar output mediated in-part by long-term depression of parallel fiber-Purkinje cell synapse and induction of long-term plasticity (LTP) in M1, leading to transient occlusion of additional LTP-like plasticity. However, little is known about the temporal dynamics of these two physiological mechanisms during motor skill learning. Here we use non-invasive brain stimulation to explore CB and M1 mechanisms during early and late motor skill learning in humans. We predicted that early skill acquisition would be proportional to cerebellar excitability (CBI) changes, whereas later stages of learning will result in M1 LTP-like plasticity modifications. We found that early, and not late into skill training, CBI changed. Whereas, occlusion of LTP-like plasticity over M1 occurred only during late, but not early training. These findings indicate a distinct temporal dissociation in the physiological role of the CB and M1 when learning a novel skill. Understanding the role and temporal dynamics of different brain regions during motor learning is critical to device optimal interventions to augment learning.

Motor learning consists of the ability to improve motor actions through practice playing a major role in the acquisition of skills required for high-performance sports or motor function recovery after brain lesions. During the last decades, it has been reported that transcranial direct-current stimulation (tDCS), consisting in applying weak direct-current through the scalp, is able of inducing polarity-specific changes in the excitability of cortical neurons. This low-cost, painless and well-tolerated portable technique has found a wide-spread use in the motor learning domain where it has been successfully applied to enhance motor learning in healthy individuals and for motor recovery after brain lesion as well as in pathological states associated to motor deficits. The main objective of this mini-review is to offer an integrative view about the potential use of tDCS for human motor learning modulation. Furthermore, we introduce the basic mechanisms underlying immediate and long-term effects associated to tDCS along with important considerations about its limitations and progression in recent years.

The cerebellum is involved in the update of motor commands during error-dependent learning. Transcranial direct current stimulation (tDCS), a form of noninvasive brain stimulation, has been shown to increase cerebellar excitability and improve learning in motor adaptation tasks. Although cerebellar involvement has been clearly demonstrated in adaptation paradigms, a type of task that heavily relies on error-dependent motor learning mechanisms, its role during motor skill learning, a behavior that likely involves error-dependent as well as reinforcement and strategic mechanisms, is not completely understood. Here, in humans, we delivered cerebellar tDCS to modulate its activity during novel motor skill training over the course of 3 d and assessed gains during training (on-line effects), between days (off-line effects), and overall improvement. We found that excitatory anodal tDCS applied over the cerebellum increased skill learning relative to sham and cathodal tDCS specifically by increasing on-line rather than off-line learning. Moreover, the larger skill improvement in the anodal group was predominantly mediated by reductions in error rate rather than changes in movement time. These results have important implications for using cerebellar tDCS as an intervention to speed up motor skill acquisition and to improve motor skill accuracy, as well as to further our understanding of cerebellar function.

Lateralization of function is an important organizational feature of the motor system. Each effector is predominantly controlled by the contralateral cerebral cortex and the ipsilateral cerebellum. Transcranial magnetic stimulation studies have revealed hemispheric differences in the stimulation strength required to evoke a muscle response from the primary motor cortex (M1), with the dominant hemisphere typically requiring less stimulation than the nondominant. The current study assessed whether the strength of the connection between the cerebellum and M1 (CB-M1), known to change in association with motor learning, have hemispheric differences and whether these differences have any behavioral correlate. We observed, in right-handed individuals, that the connection between the right cerebellum and left M1 is typically stronger than the contralateral network. Behaviorally, we detected no lateralized learning processes, though we did find a significant effect on the amplitude of reaching movements across hands. Furthermore, we observed that the strength of the CB-M1 connection is correlated with the amplitude variability of reaching movements, a measure of movement precision, where stronger connectivity was associated with better precision. These findings indicate that lateralization in the motor system is present beyond the primary motor cortex, and points to an association between cerebellar M1 connectivity and movement execution.

Introduction Recently it has been argued that two distinct interneuron networks in the primary motor cortex (M1) contribute distinctly to two varieties of physiological plasticity and motor behaviors (Hamada et al., 2014). Although one of the interneuron groups is thought to be dependent on cerebellar (CB) activity, direct physiological distinction regarding CB-M1 interactions (CBI) to these subpopulations remains poorly understood. Objectives This study assessed whether M1 coil orientation, thought to test different neuronal populations, affects CBI in the context of two motor behaviors that weight differently cerebellar vs. M1 contributions. Methods In experiment 1 (n = 10), we tested the effect of coil orientation (posterior–anterior, PA; anterior–posterior, AP) and inter-stimulus intervals (ISI: 3, 5 and 7 ms) on CBI; assessed with a conditioned TMS pulse over the cerebellum prior to TMS over the contralateral M1. In experiment 2 (n = 10), we tested how learning two distinct motor learning tasks (weighting sensorimotor calibration vs. a sequence task) affected AP- vs. PA-CBI measured at their preferential ISI. Results ANOVA-RM revealed a significant CBI effect for ISI (F(2,36) = 17.807; p Conclusion These findings indicate that CB-M1 interactions are different for the two M1 neural networks. This could be the result of either two independent CB-M1 pathways or distinct processing of cerebellar inputs within M1.