Modulation of Motor Cortical Inhibition and Facilitation by Touch Sensation from the Glabrous Skin of the Human Hand.

Touch sensation from the glabrous skin of the hand is essential for precisely controlling dexterous movements, yet the neural mechanisms by which tactile inputs influence motor circuits remain largely unexplored. By pairing air-puff tactile stimulation on the hand's glabrous skin with transcranial magnetic stimulation (TMS) over the primary motor cortex (M1), we examined the effects of tactile stimuli from single or multiple fingers on corticospinal excitability and M1's intracortical circuits. Our results showed that when we targeted the hand's first dorsal interosseous (FDI) muscle with TMS, homotopic (index finger) tactile stimulation, regardless of its point (fingertip or base), reduced corticospinal excitability. Conversely, heterotopic (ring finger) tactile stimulation had no such effect. Notably, stimulating all five fingers simultaneously led to a more pronounced decrease in corticospinal excitability than stimulating individual fingers. Furthermore, tactile stimulation significantly increased intracortical facilitation (ICF) and decreased long-interval intracortical inhibition (LICI) but did not affect short-interval intracortical inhibition (SICI). Considering the significant role of the primary somatosensory cortex (S1) in tactile processing, we also examined the effects of downregulating S1 excitability via continuous theta burst stimulation (cTBS) on tactile-motor interactions. Following cTBS, the inhibitory influence of tactile inputs on corticospinal excitability was diminished. Our findings highlight the spatial specificity of tactile inputs in influencing corticospinal excitability. Moreover, we suggest that tactile inputs distinctly modulate M1's excitatory and inhibitory pathways, with S1 being crucial in facilitating tactile-motor integration.

Personalized depth-specific neuromodulation of the human primary motor cortex via ultrasound.

Non-invasive brain stimulation has the potential to boost neuronal plasticity in the primary motor cortex (M1), but it remains unclear whether the stimulation of both superficial and deep layers of the human motor cortex can effectively promote M1 plasticity. Here, we leveraged transcranial ultrasound stimulation (TUS) to precisely target M1 circuits at depths of approximately 5 mm and 16 mm from the cortical surface. Initially, we generated computed tomography images from each participant's individual anatomical magnetic resonance images (MRI), which allowed for the generation of accurate acoustic simulations. This process ensured that personalized TUS was administered exactly to the targeted depths within M1 for each participant. Using long-term depression and long-term potentiation (LTD/LTP) theta-burst stimulation paradigms, we examined whether TUS over distinct depths of M1 could induce LTD/LTP plasticity. Our findings indicated that continuous theta-burst TUS-induced LTD-like plasticity with both superficial and deep M1 stimulation, persisting for at least 30 min. In comparison, sham TUS did not significantly alter M1 excitability. Moreover, intermittent theta-burst TUS did not result in the induction of LTP- or LTD-like plasticity with either superficial or deep M1 stimulation. These findings suggest that the induction of M1 plasticity can be achieved with ultrasound stimulation targeting distinct depths of M1, which is contingent on the characteristics of TUS. KEY POINTS: The study integrated personalized transcranial ultrasound stimulation (TUS) with electrophysiology to determine whether TUS targeting superficial and deep layers of the human motor cortex (M1) could elicit long-term depression (LTD) or long-term potentiation (LTP) plastic changes. Utilizing acoustic simulations derived from individualized pseudo-computed tomography scans, we ensured the precision of TUS delivery to the intended M1 depths for each participant. Continuous theta-burst TUS targeting both the superficial and deep layers of M1 resulted in the emergence of LTD-like plasticity, lasting for at least 30 min. Administering intermittent theta-burst TUS to both the superficial and deep layers of M1 did not lead to the induction of LTP- or LTD-like plastic changes. We suggest that theta-burst TUS targeting distinct depths of M1 can induce plasticity, but this effect is dependent on specific TUS parameters.

Memory consolidation of sequence learning and dynamic adaptation during wakefulness.

Motor learning involves acquiring new movement sequences and adapting motor commands to novel conditions. Labile motor memories, acquired through sequence learning and dynamic adaptation, undergo a consolidation process during wakefulness after initial training. This process stabilizes the new memories, leading to long-term memory formation. However, it remains unclear if the consolidation processes underlying sequence learning and dynamic adaptation are independent and if distinct neural regions underpin memory consolidation associated with sequence learning and dynamic adaptation. Here, we first demonstrated that the initially labile memories formed during sequence learning and dynamic adaptation were stabilized against interference through time-dependent consolidation processes occurring during wakefulness. Furthermore, we found that sequence learning memory was not disrupted when immediately followed by dynamic adaptation and vice versa, indicating distinct mechanisms for sequence learning and dynamic adaptation consolidation. Finally, by applying patterned transcranial magnetic stimulation to selectively disrupt the activity in the primary motor (M1) or sensory (S1) cortices immediately after sequence learning or dynamic adaptation, we found that sequence learning consolidation depended on M1 but not S1, while dynamic adaptation consolidation relied on S1 but not M1. For the first time in a single experimental framework, this study revealed distinct neural underpinnings for sequence learning and dynamic adaptation consolidation during wakefulness, with significant implications for motor skill enhancement and rehabilitation.

Motor unit activity and synaptic inputs to motoneurons in the caudal part of the injured spinal cord.

Spinal cord injury (SCI) disrupts neuronal function below the lesion epicenter, causing disuse muscle atrophy. We investigated motor unit (MU) activity and synaptic inputs to motoneurons in the caudal region of the injured spinal cord. Participants with C4-C7 cervical injuries were studied. The extensor digitorum communis (EDC) muscle, which is mainly innervated by C8, was assessed for disuse muscle atrophy. Using advanced electromyography and signal-processing techniques, we examined the concurrent activation of a substantial population of MUs during force-tracking tasks. We found that in participants with SCI (n = 9), both MU discharge rates and the amplitudes of MU action potentials were significantly lower than in controls (n = 9). After SCI, MUs were recruited in a limited force range as the strength of muscle contractions increased, implying a disruption in the orderly MU recruitment pattern. Coherence analysis revealed reduced synaptic inputs to motoneurons in the delta band (0.5-5 Hz) for participants with SCI, suggesting diminished common synaptic inputs to the EDC muscle. In addition, participants with SCI exhibited greater muscle force variability. Using principal component analysis on low-frequency MU discharge rates, we found that the first common component (FCC) captured the most discharge variability in participants with SCI. The coefficients of variation (CV) of the FCC correlated with force signal CVs, suggesting force variability mainly results from common synaptic inputs to the EDC muscle after SCI. These results advance our understanding of the neurophysiology of disuse muscle atrophy in human SCI, paving the way for therapeutic interventions to restore muscle function.NEW & NOTEWORTHY This study analyzed motor unit (MU) function below the lesion epicenter in patients with spinal cord injury (SCI). We found reduced MU discharge rates and action potential amplitudes in participants with SCI compared with controls. The strength of common synaptic inputs to motoneurons was reduced in patients with SCI, with increased force variability primarily due to low-frequency oscillations of common inputs. This study enhances understanding of neurophysiological and behavioral changes in disuse muscle atrophy post-SCI.

Effects of transcranial direct current stimulation over human motor cortex on cognitive-motor and sensory-motor functions.

The primary motor cortex (M1) is broadly acknowledged for its crucial role in executing voluntary movements. Yet, its contributions to cognitive and sensory functions remain largely unexplored. Transcranial direct current stimulation (tDCS) is a noninvasive neurostimulation method that can modify brain activity, thereby enabling the establishment of a causal link between M1 activity and behavior. This study aimed to investigate the online effects of tDCS over M1 on cognitive-motor and sensory-motor functions. Sixty-four healthy participants underwent either anodal or sham tDCS while concurrently performing a set of standardized robotic tasks. These tasks provided sensitive and objective assessments of brain functions, including action selection, inhibitory control, cognitive control of visuomotor skills, proprioceptive sense, and bimanual coordination. Our results revealed that anodal tDCS applied to M1 enhances decision-making capacity in selecting appropriate motor actions and avoiding distractors compared to sham stimulation, suggesting improved action selection and inhibitory control capabilities. Furthermore, anodal tDCS reduces the movement time required to accomplish bimanual movements, suggesting enhanced bimanual performance. However, we found no impact of anodal tDCS on cognitive control of visuomotor skills and proprioceptive sense. This study suggests that augmenting M1 activity via anodal tDCS influences cognitive-motor and sensory-motor functions in a task-dependent manner.

Memory decay and generalization following distinct motor learning mechanisms.

Motor skill learning is considered to arise out of contributions from multiple learning mechanisms, including error-based learning (EBL), use-dependent learning (UDL), and reinforcement learning (RL). These learning mechanisms exhibit dissociable roles and engage different neural circuits during skill acquisition. However, it remains largely unknown how a newly formed motor memory acquired through each learning mechanism decays over time and whether distinct learning mechanisms produce different generalization patterns. Here, we used variants of reaching paradigms that dissociated these learning mechanisms to examine the time course of memory decay following each learning and the generalization patterns of each learning. We found that motor memories acquired through these learning mechanisms decayed as a function of time. Notably, 15 min, 6 h, and 24 h after acquisition, the memory of EBL decayed much greater than that of RL. The memory acquired through UDL faded away within a few minutes. Motor memories formed through EBL and RL for given movement directions generalized to untrained movement directions, with the generalization of EBL being greater than that of RL. In contrast, motor memory of UDL could not generalize to untrained movement directions. These results suggest that distinct learning mechanisms exhibit different patterns of memory decay and generalization.NEW & NOTEWORTHY Motor skill learning is likely to involve error-based learning, use-dependent plasticity, and operant reinforcement. Here, we showed that these dissociable learning mechanisms exhibited distinct patterns of memory decay and generalization. With a better understanding of the characteristics of these learning mechanisms, it becomes possible to regulate each learning process separately to improve neurological rehabilitation.

Generalization of visuomotor adaptation associated with use-dependent learning across different movement workspaces and limb postures.

Use-dependent learning has been investigated to some extent, although how motor patterns obtained through use-dependent learning are generalized across different movement conditions remains to be further understood. Here, we investigate the generalizability of use-dependent learning by determining how visuomotor adaptation associated with use-dependent learning was generalized across different workspaces and limb postures. In our experiments, participants first adapted to a visuomotor rotation while reaching from a given starting position toward a training target in a given limb posture. They concurrently experienced repetitive passive movements from varying starting positions (Exp. 1) or in varying limb postures (Exp. 2). Following that, they adapted to the same rotation while reaching from the original start circle to a transfer target. Regardless of the workspaces or limb postures experienced, passive training facilitated visuomotor adaptation in the transfer session, indicating that visuomotor adaptation can generalize across different movement conditions. However, the extent of generalization decreased as the experienced workspaces or limb postures deviated from the original condition experienced. Our findings indicate that use-dependent learning results in motor instances that are workspace and limb-posture specific, although they are still useful for enhancing the generalization of motor learning across varying conditions.

Differences in motor unit recruitment patterns and low frequency oscillation of discharge rates between unilateral and bilateral isometric muscle contractions.

INTRODUCTION: Distinct cortical activities contribute to unilateral and bilateral motor control. However, it remains largely unknown whether the behavior of motor neurons differs between unilateral and bilateral isometric force generation. Here, we first investigated motor units (MUs) recruitment patterns during unilateral and bilateral force generation. Considering that the force control is primarily regulated by low-frequency synaptic inputs to motor neurons, we also examined the relation between MU discharge rate and force output during unilateral and bilateral muscle contractions. METHODS: Using advanced electromyography (EMG) sensor arrays and spike-triggered averaging techniques, we examined a large population of MUs in the right first dorsal interosseous (FDI) muscle during unilateral and bilateral force tracking tasks. Using the principal component analysis, we analyzed the first common component (FCC) of MU discharge rate to describe the force fluctuations during unilateral and bilateral contractions. RESULTS: We found that MU discharge rate decreased during bilateral compared with unilateral contractions. MU recruitment threshold increased, while the amplitude and duration of MU action potential (MUAP) remained unchanged during bilateral compared with unilateral contractions. We found that the coefficients of variation (CV) for the force and FCC signal increased during bilateral compared with unilateral contractions. Notably, the FCC signal captured a great amount of MU discharge variability, and its CV correlated with the CV of the force signal. CONCLUSION: Our findings suggest that MU recruitment patterns are altered during bilateral compared with unilateral isometric force generation, likely related to changes at the low-frequency portion of the synaptic drive.

The decay and consolidation of effector-independent motor memories.

Learning a motor adaptation task produces intrinsically unstable or transient motor memories. Despite the presence of effector-independent motor memories following the learning of novel environmental dynamics, it remains largely unknown how those memory traces decay in different contexts and whether an "offline" consolidation period protects memories against decay. Here, we exploit inter-effector transfer to address these questions. We found that newly acquired motor memories formed with one effector could be partially retrieved by the untrained effector to enhance its performance when the decay occurred with the passage of time or "washout" trials on which error feedback was provided. The decay of motor memories was slower following "error-free" trials, on which errors were artificially clamped to zero or removed, compared with "washout" trials. However, effector-independent memory components were abolished following movements made in the absence of task errors, resulting in no transfer gains. The brain can stabilize motor memories during daytime wakefulness. We found that 6 h of wakeful resting increased the resistance of effector-independent memories to decay. Collectively, our results suggest that the decay of effector-independent motor memories is context-dependent, and offline processing preserves those memories against decay, leading to improvements of the subsequent inter-effector transfer.

The nature of savings associated with a visuomotor adaptation task that involves one arm or both arms.

The nature of savings in visuomotor adaptation is typically studied using a paradigm in which one arm experiences multiple conditions such as adaptation, washout and readaptation. It has seldom been studied, however, using a paradigm that involves both arms. Here, we examined the effect of (1) using different arms and (2) the availability of visual feedback during a washout session following visuomotor adaptation on savings. We first had healthy young adults adapt to a visuomotor rotation condition during reaching movements with the left arm. Following that, they experienced a washout session with either the left or right arm, with or without visual feedback, and then the readaptation session with the left arm again. We hypothesized that if savings occurred due to the explicit recall of cognitive strategies, the pattern of savings would be similar regardless of which arm was used during the washout session. Results showed that in terms of the percentage of savings, there was a significant difference between the conditions in which the left or right arm was used during the washout, but not between the conditions in which visual feedback was provided or absent. In terms of the rate of relearning, a significant difference was observed between the conditions in which the left or right arm was used during the washout, and also between the conditions in which visual feedback was provided or absent. These findings suggest that the explicit recall of strategies is not the only source for savings and further suggest that effector-specific, use-dependent learning can also contribute to savings.

The Interactions Between Primary Somatosensory and Motor Cortex during Human Grasping Behaviors.

Afferent inputs to the primary somatosensory cortex (S1) are differentially processed during precision and power grip in humans. However, it remains unclear how S1 interacts with the primary motor cortex (M1) during these two grasping behaviors. To address this question, we measured short-latency afferent inhibition (SAI), reflecting S1-M1 interactions via thalamo-cortical pathways, using paired-pulse transcranial magnetic stimulation (TMS) during precision and power grip. The TMS coil over the hand representation of M1 was oriented in the posterior-anterior (PA) and anterior-posterior (AP) direction to activate distinct sets of corticospinal neurons. We found that SAI increased during precision compared with power grip when AP, but not PA, currents were applied. Notably, SAI tested in the AP direction were similar during two-digit than five-digit precision grip. The M1 receives movement information from S1 through direct cortico-cortical pathways, so intra-hemispheric S1-M1 interactions using dual-site TMS were also evaluated. Stimulation of S1 attenuated M1 excitability (S1-M1 inhibition) during precision and power grip, while the S1-M1 inhibition ratio remained similar across tasks. Taken together,our findings suggest that distinct neural mechanisms for S1-M1 interactions mediate precision and power grip, presumably by modulating neural activity along thalamo-cortical pathways.

Consolidation of use-dependent motor memories induced by passive movement training.

Motor adaptation, a type of motor learning, is often thought to involve two distinct processes: error-based and use-dependent learning. Passive movement training, which is associated with use-dependent learning, can facilitate motor adaptation, although it is unknown how long its facilitative effect can last. The objective of this study was to examine the lasting effect of passive training on visuomotor adaptation for the duration of up to 24 h. Neurotypical, right-handed subjects experienced four experimental sessions: baseline, training, time delay and testing. In the training session, all subjects received passive training of their dominant arm that was moved by an exoskeletal robot in a "desired" target direction repeatedly. Following that, the subjects experienced a time delay of 5 min, 1 h or 24 h. In the testing session, the subjects performed reaching movements under a novel visuomotor condition, in which the visual display was rotated 30 degrees counterclockwise about the start circle. Control subjects experienced the baseline and testing sessions with a time delay of 5 min between the two sessions. Results indicate that the 1-h and 24-h groups, but not the 5-min group, adapted to the rotation significantly better than the controls. This finding has an implication for neurorehabilitation suggesting, for example, that passive proprioceptive training may indeed be a viable option for improving arm motor function in stroke survivors with severe hemiparesis, for whom efficient intervention techniques are very limited.

Lack of interlimb transfer following visuomotor adaptation in a person with congenital mirror movements.

Congenital mirror movements (CMMs) have been traditionally thought to occur due to the corticospinal tracts that project abnormally to both sides of the body. More recently, it has been suggested that both brain hemispheres are activated during intended unilateral movements due to deficient transcallosal inhibition, leading to mirror movements on the unintended side as well. To further understand the mechanisms underlying CMMs, we examined the pattern of interlimb transfer following visuomotor adaptation in 'DB', an individual with CMMs. DB's CMMs were confirmed by detecting EMG signals in both arms during intended unilateral movements, and also when transcranial magnetic stimulation (TMS) was applied to the motor cortex. Following that, DB performed reaching movements with the left arm under a visuomotor condition in which the visual display was rotated 30° counterclockwise about the start circle, and then with the right arm under the same (experiment 1) or opposing (experiment 2) rotation condition. DB's performances were compared with the data from control subjects. In both experiments, DB was able to adapt to the rotation with either arm; however, movement errors at the beginning of right-arm adaptation did not differ from those at the beginning of left-arm adaptation, indicating no transfer. These transfer patterns differ from those observed in controls, who demonstrated substantial transfer when the rotation directions were the same between the arms, but no transfer when they were opposite. These findings suggest that in DB, both hemispheres are activated during unilateral movements, but interhemispheric communication is impaired, thus resulting in mirror movements on the involuntary side.

Lack of generalization between explicit and implicit visuomotor learning.

Visuomotor adaptation has been thought to occur implicitly, although recent findings suggest that it involves both explicit and implicit processes. Here, we investigated generalization between an explicit condition, in which subjects reached toward imaginary targets under a veridical visuomotor condition, and an implicit condition, in which subjects reached toward visual targets under a 30-degree counterclockwise rotation condition. In experiment 1, two groups of healthy young adults first experienced either the explicit or the implicit condition, then the other condition. The third group experienced the explicit, then the implicit condition with an instruction that the same cognitive strategy could be used in both conditions. Results showed that initial explicit learning did not facilitate subsequent implicit learning, or vice versa, in the first two groups. Subjects in the third group performed better at the beginning of the implicit condition, but still had to adapt to the rotation gradually. In experiment 2, three additional subject groups were tested. One group experienced the explicit, then an implicit condition in which the rotation direction was opposite (30-degree clockwise rotation). Generalization between the conditions was still minimal in that group. Two other groups experienced either the explicit or implicit condition, then performed reaching movements without visual feedback. Those who experienced the explicit condition did not demonstrate aftereffects, while those who experienced the implicit condition did. Collectively, these findings suggest that visuomotor adaptation primarily involves implicit processes, and that explicit processes can add up in a complementary fashion as individuals become increasingly aware of the perturbation.

Enhancing Generalization of Visuomotor Adaptation by Inducing Use-dependent Learning.

Learning a motor task in one condition typically generalizes to another, although it is unclear why it generalizes substantially in certain situations, but only partially in other situations (e.g., across movement directions and motor effectors). Here, we demonstrate that generalization of motor learning across directions and effectors can be enhanced substantially by inducing use-dependent learning, that is, by having subjects experience motor actions associated with a desired trajectory repeatedly during reaching movements. In Experiments 1 and 2, healthy human adults adapted to a visuomotor rotation while concurrently experiencing repetitive passive movements guided by a robot. This manipulation increased the extent of generalization across movement directions (Expt. 1) and across the arms (Expt. 2) by up to 50% and 42%, respectively, indicating crucial contribution of use-dependent learning to motor generalization. In Experiment 3, we applied repetitive transcranial magnetic stimulation (rTMS) to the left primary motor cortex (M1) of the human subjects prior to passive training with the right arm to increase cortical excitability. This intervention resulted in increased motor-evoked potentials (MEPs) and decreased short-interval intracortical inhibition (SICI) in the rTMS group, but not in the sham group. These changes observed in the rTMS group were accompanied by enhanced generalization of visuomotor adaptation across the arms, which was not the case in the sham group. Collectively, these findings confirm the involvement of M1 in use-dependent learning, and suggest that use-dependent learning can contribute not only to motor learning, but also to motor generalization.

Experiencing a reaching task passively with one arm while adapting to a visuomotor rotation with the other can lead to substantial transfer of motor learning across the arms.

The extent of transfer following visuomotor adaptation across the arms is typically limited as compared to that within the same arm. However, we have demonstrated that interlimb transfer can occur nearly completely if one arm performs reaching movements associated with a desired trajectory repeatedly and actively during an initial training session in which the other arm adapts to a novel visuomotor adaptation. Based on that finding, we argued that the absence of instances associated with specific motor effectors is the major reason for limited interlimb transfer. Here, we examined whether providing movement instances associated with one arm passively while adapting to a visuomotor rotation with the opposite arm could also lead to a greater extent of interlimb transfer. We had subjects perform reaching movements either actively or passively with the right arm while adapting to a 30° visuomotor rotation with the left arm (training session), and then had them perform reaching movements under the rotation condition with the right arm (transfer session). Results showed that the extent of transfer observed in the active and the passive training groups was significantly greater than that observed in a control group who only experienced the testing session. This finding suggests that providing effector-specific instances can increase the extent of interlimb transfer substantially, regardless of whether the instances are provided actively or passively. The current finding may have implications for neurorehabilitation targeted for individuals with motor impairment, such as persons with stroke or spinal cord injury.

The combined effects of action observation and passive proprioceptive training on adaptive motor learning.

Sensorimotor adaptation can be induced by action observation, and also by passive training. Here, we investigated the effect of a protocol that combined action observation and passive training on visuomotor adaptation, by comparing it with the effect of action observation or passive training alone. Subjects were divided into five conditions during the training session: (1) action observation, in which the subjects watched a video of a model who adapted to a novel visuomotor rotation; (2) proprioceptive training, in which the subject's arm was moved passively to target locations that were associated with desired trajectories; (3) combined training, in which the subjects watched the video of a model during a half of the session and experienced passive movements during the other half; (4) active training, in which the subjects adapted actively to the rotation; and (5) a control condition, in which the subjects did not perform any task. Following that session, all subjects adapted to the same visuomotor rotation. Results showed that the subjects in the combined training condition adapted to the rotation significantly better than those in the observation or proprioceptive training condition, although their performance was not as good as that of those who adapted actively. These findings suggest that although a protocol that combines action observation and passive training consists of all the processes involved in active training (error detection and correction, effector-specific and proprioceptively based reaching movements), these processes in that protocol may work differently as compared to a protocol in which the same processes are engaged actively.