Consolidation of dynamic motor learning is not disrupted by rTMS of primary motor cortex

Motor skills, once learned, are often retained over a long period of time. However, such learning first undergoes a period of consolidation after practice. During this time, the motor memory is susceptible to being disrupted by the performance of another motor-learning task. Recently, it was shown that repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex could disrupt the retention of a newly learned ballistic task in which subjects had to oppose their index finger and thumb as rapidly as possible. Here we investigate whether the motor cortex is similarly involved during the consolidation that follows learning novel dynamics. We applied rTMS to primary motor cortex shortly after subjects had either learned to compensate for a dynamic force field applied to their index finger or learned a ballistic finger abduction task. rTMS severely degraded the retention of the learning for the ballistic task but had no effect on retention of the dynamic force-field learning. This suggests that, unlike learning of simple ballistic skills, learning of dynamics may be stored in a more distributed manner, possibly outside the primary motor cortex.     

Altered Synaptic Plasticity in Tourette's Syndrome and Its Relationship to Motor Skill Learning

Gilles de la Tourette syndrome is a neuropsychiatric disorder characterized by motor and phonic tics that can be considered motor responses to preceding inner urges. It has been shown that Tourette patients have inferior performance in some motor learning tasks and reduced synaptic plasticity induced by transcranial magnetic stimulation. However, it has not been investigated whether altered synaptic plasticity is directly linked to impaired motor skill acquisition in Tourette patients. In this study, cortical plasticity was assessed by measuring motor-evoked potentials before and after paired associative stimulation in 14 Tourette patients (13 male; age 18–39) and 15 healthy controls (12 male; age 18–33). Tic and urge severity were assessed using the Yale Global Tic Severity Scale and the Premonitory Urges for Tics Scale. Motor learning was assessed 45 minutes after inducing synaptic plasticity and 9 months later, using the rotary pursuit task. On average, long-term potentiation-like effects in response to the paired associative stimulation were present in healthy controls but not in patients. In Tourette patients, long-term potentiation-like effects were associated with more and long-term depression-like effects with less severe urges and tics. While motor learning did not differ between patients and healthy controls 45 minutes after inducing synaptic plasticity, the learning curve of the healthy controls started at a significantly higher level than the Tourette patients'' 9 months later. Induced synaptic plasticity correlated positively with motor skills in healthy controls 9 months later. The present study confirms previously found long-term improvement in motor performance after paired associative stimulation in healthy controls but not in Tourette patients. Tourette patients did not show long-term potentiation in response to PAS and also showed reduced levels of motor skill consolidation after 9 months compared to healthy controls. Moreover, synaptic plasticity appears to be related to symptom severity.     

Learning-induced improvement in encoding and decoding of specific movement directions by neurons in the primary motor cortex

Many recent studies describe learning-related changes in sensory and motor areas, but few have directly probed for improvement in neuronal coding after learning. We used information theory to analyze single-cell activity from the primary motor cortex of monkeys, before and after learning a local rotational visuomotor task. We show that after learning, neurons in the primary motor cortex conveyed more information about the direction of movement and did so with relation to their directional sensitivity. Similar to recent findings in sensory systems, this specific improvement in encoding is correlated with an increase in the slope of the neurons' tuning curve. We further demonstrate that the improved information after learning enables a more accurate reconstruction of movement direction from neuronal populations. Our results suggest that similar mechanisms govern learning in sensory and motor areas and provide further evidence for a tight relationship between the locality of learning and the properties of neurons; namely, cells only show plasticity if their preferred direction is near the training one. The results also suggest that simple learning tasks can enhance the performance of brain–machine interfaces.     

Impairment of auditory-motor timing and compensatory reorganization after ventral premotor cortex stimulation

Integrating auditory and motor information often requires precise timing as in speech and music. In humans, the position of the ventral premotor cortex (PMv) in the dorsal auditory stream renders this area a node for auditory-motor integration. Yet, it remains unknown whether the PMv is critical for auditory-motor timing and which activity increases help to preserve task performance following its disruption. 16 healthy volunteers participated in two sessions with fMRI measured at baseline and following rTMS (rTMS) of either the left PMv or a control region. Subjects synchronized left or right finger tapping to sub-second beat rates of auditory rhythms in the experimental task, and produced self-paced tapping during spectrally matched auditory stimuli in the control task. Left PMv rTMS impaired auditory-motor synchronization accuracy in the first sub-block following stimulation (p<0.01, Bonferroni corrected), but spared motor timing and attention to task. Task-related activity increased in the homologue right PMv, but did not predict the behavioral effect of rTMS. In contrast, anterior midline cerebellum revealed most pronounced activity increase in less impaired subjects. The present findings suggest a critical role of the left PMv in feed-forward computations enabling accurate auditory-motor timing, which can be compensated by activity modulations in the cerebellum, but not in the homologue region contralateral to stimulation.     

Sleep-Dependent Reactivation of Ensembles in Motor Cortex Promotes Skill Consolidation

Despite many prior studies demonstrating offline behavioral gains in motor skills after sleep, the underlying neural mechanisms remain poorly understood. To investigate the neurophysiological basis for offline gains, we performed single-unit recordings in motor cortex as rats learned a skilled upper-limb task. We found that sleep improved movement speed with preservation of accuracy. These offline improvements were linked to both replay of task-related ensembles during non-rapid eye movement (NREM) sleep and temporal shifts that more tightly bound motor cortical ensembles to movements; such offline gains and temporal shifts were not evident with sleep restriction. Interestingly, replay was linked to the coincidence of slow-wave events and bursts of spindle activity. Neurons that experienced the most consistent replay also underwent the most significant temporal shift and binding to the motor task. Significantly, replay and the associated performance gains after sleep only occurred when animals first learned the skill; continued practice during later stages of learning (i.e., after motor kinematics had stabilized) did not show evidence of replay. Our results highlight how replay of synchronous neural activity during sleep mediates large-scale neural plasticity and stabilizes kinematics during early motor learning.     

Neural mechanisms of reward-related motor learning

The analysis of the neural mechanisms responsible for reward-related learning has benefited from recent studies of the effects of dopamine on synaptic plasticity. Dopamine-dependent synaptic plasticity may lead to strengthening of selected inputs on the basis of an activity-dependent conjunction of sensory afferent activity, motor output activity, and temporally related firing of dopamine cells. Such plasticity may provide a link between the reward-related firing of dopamine cells and the acquisition of changes in striatal cell activity during learning. This learning mechanism may play a special role in the translation of reward signals into context-dependent response probability or directional bias in movement responses.     

Rethinking motor learning and savings in adaptation paradigms: model-free memory for successful actions combines with internal models

Although motor learning is likely to involve multiple processes, phenomena observed in error-based motor learning paradigms tend to be conceptualized in terms of only a single process: adaptation, which occurs through updating an internal model. Here we argue that fundamental phenomena like movement direction biases, savings (faster relearning), and interference do not relate to adaptation but instead are attributable to two additional learning processes that can be characterized as model-free: use-dependent plasticity and operant reinforcement. Although usually "hidden" behind adaptation, we demonstrate, with modified visuomotor rotation paradigms, that these distinct model-based and model-free processes combine to learn an error-based motor task. (1) Adaptation of an internal model channels movements toward successful error reduction in visual space. (2) Repetition of the newly adapted movement induces directional biases toward the?repeated movement. (3) Operant reinforcement through association of the adapted movement with successful error reduction is responsible for savings.     

Theta burst stimulation of the human motor cortex

It has been 30 years since the discovery that repeated electrical stimulation of neural pathways can lead to long-term potentiation in hippocampal slices. With its relevance to processes such as learning and memory, the technique has produced a vast literature on mechanisms of synaptic plasticity in animal models. To date, the most promising method for transferring these methods to humans is repetitive transcranial magnetic stimulation (rTMS), a noninvasive method of stimulating neural pathways in the brain of conscious subjects through the intact scalp. However, effects on synaptic plasticity reported are often weak, highly variable between individuals, and rarely last longer than 30 min. Here we describe a very rapid method of conditioning the human motor cortex using rTMS that produces a controllable, consistent, long-lasting, and powerful effect on motor cortex physiology and behavior after an application period of only 20-190 s.     

Effect of nitric oxide synthase inhibition on the manipulative behaviour of Sepia officinalis

Nitric oxide (NO), produced by nitric oxide synthase (NOS) in brain tissue, is essential for a variety of kinds of learning in vertebrates. In invertebrates, there are clear examples of an association between NO signalling and olfaction, feeding behaviour and learning. The role of NO as a neurotransmitter in the manipulative behaviour of Sepia officinalis was tested. Manipulative behaviour requires extensive chemotactile sensory processing, fine motor control and probably motor learning processes. NADPH-diaphorase activity (a reliable histochemical marker for nitric oxide synthase) was found in sensory epithelia and in the axial nerve cord of the arms. NOS inhibitor injections (L-NAME) produced an increase in the latency of prey paralysis. By placing mechanical constraints on the base of the fifth periopods of the crab, we prevented the cuttlefish from injecting cephalotoxin and, thus, forced it to change injection sites. We showed that L-NAME pretreatment did not affect the flexibility of the manipulative behaviour. The implications of the involvement of NO in the acquisition of chemo-tactile information and in the programming of the motor skills of the manipulative behaviour is discussed.     

Excitability decreasing central motor plasticity is retained in multiple sclerosis patients

ABSTRACT: BACKGROUND: Compensation of brain injury in multiple sclerosis (MS) may in part work through mechanisms involving neuronal plasticity on local and interregional scales. Mechanisms limiting excessive neuronal activity may have special significance for retention and (re-)acquisition of lost motor skills in brain injury. However, previous neurophysiological studies of plasticity in MS have investigated only excitability enhancing plasticity and results from neuroimaging are ambiguous. Thus, the aim of this study was to probe long-term depression-like central motor plasticity utilizing continuous theta-burst stimulation (cTBS), a non-invasive brain stimulation protocol. Because cTBS also may trigger behavioral effects through local interference with neuronal circuits, this approach also permitted investigating the functional role of the primary motor cortex (M1) in force control in patients with MS. METHODS: We used cTBS and force recordings to examine long-term depression-like central motor plasticity and behavioral consequences of a M1 lesion in 14 patients with stable mild-to-moderate MS (median EDSS 1.5, range 0 to 3.5) and 14 age-matched healthy controls. cTBS consisted of bursts (50 Hz) of three subthreshold biphasic magnetic stimuli repeated at 5 Hz for 40 s over the hand area of the left M1. Corticospinal excitability was probed via motor-evoked potentials (MEP) in the abductor pollicis brevis muscle over M1 before and after cTBS. Force production performance was assessed in an isometric right thumb abduction task by recording the number of hits into a predefined force window. RESULTS: cTBS reduced MEP amplitudes in the contralateral abductor pollicis brevis muscle to a comparable extent in control subjects (69 +/- 22 % of baseline amplitude, p < 0.001) and in MS patients (69 +/- 18 %, p < 0.001). In contrast, post-cTBS force production performance was only impaired in controls (2.2 +/- 2.8, p = 0.011), but not in MS patients (2.0 +/- 4.4, p = 0.108). The decline in force production performance following cTBS correlated with corticomuscular latencies (CML) in MS patients, but did not correlate with MEP amplitude reduction in patients or controls. CONCLUSIONS: Long-term depression-like plasticity remains largely intact in mild-to-moderate MS. Increasing brain injury may render the neuronal networks less responsive toward lesion-induction by cTBS.     

Effects of Sensory Behavioral Tasks on Pain Threshold and Cortical Excitability

Background/Objective

Transcutaneous electrical stimulation has been proven to modulate nervous system activity, leading to changes in pain perception, via the peripheral sensory system, in a bottom up approach. We tested whether different sensory behavioral tasks induce significant effects in pain processing and whether these changes correlate with cortical plasticity.

Methodology/Principal Findings

This randomized parallel designed experiment included forty healthy right-handed males. Three different somatosensory tasks, including learning tasks with and without visual feedback and simple somatosensory input, were tested on pressure pain threshold and motor cortex excitability using transcranial magnetic stimulation (TMS). Sensory tasks induced hand-specific pain modulation effects. They increased pain thresholds of the left hand (which was the target to the sensory tasks) and decreased them in the right hand. TMS showed that somatosensory input decreased cortical excitability, as indexed by reduced MEP amplitudes and increased SICI. Although somatosensory tasks similarly altered pain thresholds and cortical excitability, there was no significant correlation between these variables and only the visual feedback task showed significant somatosensory learning.

Conclusions/Significance

Lack of correlation between cortical excitability and pain thresholds and lack of differential effects across tasks, but significant changes in pain thresholds suggest that analgesic effects of somatosensory tasks are not primarily associated with motor cortical neural mechanisms, thus, suggesting that subcortical neural circuits and/or spinal cord are involved with the observed effects. Identifying the neural mechanisms of somatosensory stimulation on pain may open novel possibilities for combining different targeted therapies for pain control.     

Learning the same motor task twice impairs its retention in a time- and dose-dependent manner

Anterograde interference emerges when two differing tasks are learned in close temporal proximity, an effect repeatedly attributed to a competition between differing task memories. However, recent development alternatively suggests that initial learning may trigger a refractory period that occludes neuroplasticity and impairs subsequent learning, consequently mediating interference independently of memory competition. Accordingly, this study tested the hypothesis that interference can emerge when the same motor task is being learned twice, that is when competition between memories is prevented. In a first experiment, the inter-session interval (ISI) between two identical motor learning sessions was manipulated to be 2 min, 1 h or 24 h. Results revealed that retention of the second session was impaired as compared to the first one when the ISI was 2 min but not when it was 1 h or 24 h, indicating a time-dependent process. Results from a second experiment replicated those of the first one and revealed that adding a third motor learning session with a 2 min ISI further impaired retention, indicating a dose-dependent process. Results from a third experiment revealed that the retention impairments did not take place when a learning session was preceded by simple rehearsal of the motor task without concurrent learning, thus ruling out fatigue and confirming that retention is impaired specifically when preceded by a learning session. Altogether, the present results suggest that competing memories is not the sole mechanism mediating anterograde interference and introduce the possibility that a time- and dose-dependent refractory period—independent of fatigue—also contributes to its emergence. One possibility is that learning transiently perturbs the homeostasis of learning-related neuronal substrates. Introducing additional learning when homeostasis is still perturbed may not only impair performance improvements, but also memory formation.     

Illusory sensation of movement induced by repetitive transcranial magnetic stimulation

Human movement sense relies on both somatosensory feedback and on knowledge of the motor commands used to produce the movement. We have induced a movement illusion using repetitive transcranial magnetic stimulation over primary motor cortex and dorsal premotor cortex in the absence of limb movement and its associated somatosensory feedback. Afferent and efferent neural signalling was abolished in the arm with ischemic nerve block, and in the leg with spinal nerve block. Movement sensation was assessed following trains of high-frequency repetitive transcranial magnetic stimulation applied over primary motor cortex, dorsal premotor cortex, and a control area (posterior parietal cortex). Magnetic stimulation over primary motor cortex and dorsal premotor cortex produced a movement sensation that was significantly greater than stimulation over the control region. Movement sensation after dorsal premotor cortex stimulation was less affected by sensory and motor deprivation than was primary motor cortex stimulation. We propose that repetitive transcranial magnetic stimulation over dorsal premotor cortex produces a corollary discharge that is perceived as movement.     

Cross-Limb Interference during Motor Learning

It is well known that following skill learning, improvements in motor performance may transfer to the untrained contralateral limb. It is also well known that retention of a newly learned task A can be degraded when learning a competing task B that takes place directly after learning A. Here we investigate if this interference effect can also be observed in the limb contralateral to the trained one. Therefore, five different groups practiced a ballistic finger flexion task followed by an interfering visuomotor accuracy task with the same limb. Performance in the ballistic task was tested before the training, after the training and in an immediate retention test after the practice of the interference task for both the trained and the untrained hand. After training, subjects showed not only significant learning and interference effects for the trained limb but also for the contralateral untrained limb. Importantly, the interference effect in the untrained limb was dependent on the level of skill acquisition in the interfering motor task. These behavioural results of the untrained limb were accompanied by training specific changes in corticospinal excitability, which increased for the hemisphere ipsilateral to the trained hand following ballistic training and decreased during accuracy training of the ipsilateral hand. The results demonstrate that contralateral interference effects may occur, and that interference depends on the level of skill acquisition in the interfering motor task. This finding might be particularly relevant for rehabilitation.     

Effects of chronic iTBS‐rTMS and enriched environment on visual cortex early critical period and visual pattern discrimination in dark‐reared rats

Early cortical critical period resembles a state of enhanced neuronal plasticity enabling the establishment of specific neuronal connections during first sensory experience. Visual performance with regard to pattern discrimination is impaired if the cortex is deprived from visual input during the critical period. We wondered how unspecific activation of the visual cortex before closure of the critical period using repetitive transcranial magnetic stimulation (rTMS) could affect the critical period and the visual performance of the experimental animals. Would it cause premature closure of the plastic state and thus worsen experience‐dependent visual performance, or would it be able to preserve plasticity? Effects of intermittent theta‐burst stimulation (iTBS) were compared with those of an enriched environment (EE) during dark‐rearing (DR) from birth. Rats dark‐reared in a standard cage showed poor improvement in a visual pattern discrimination task, while rats housed in EE or treated with iTBS showed a performance indistinguishable from rats reared in normal light/dark cycle. The behavioral effects were accompanied by correlated changes in the expression of brain‐derived neurotrophic factor (BDNF) and atypical PKC (PKCζ/PKMζ), two factors controlling stabilization of synaptic potentiation. It appears that not only nonvisual sensory activity and exercise but also cortical activation induced by rTMS has the potential to alleviate the effects of DR on cortical development, most likely due to stimulation of BDNF synthesis and release. As we showed previously, iTBS reduced the expression of parvalbumin in inhibitory cortical interneurons, indicating that modulation of the activity of fast‐spiking interneurons contributes to the observed effects of iTBS. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 19–33, 2016     

Sensory interaction with central ‘generators’ during respiration in the dogfish

Summary The activity in sensory and motor nerves of the gills was recorded from selected branches of the vagus nerve in decerebrate dogfish,Scyliorhinus canicula. Vagal motoneuronal activity was observed at the start of the rapid pharyngeal contraction and was followed by sensory nerve activity which preceded the slow expansion phase. Rhythmical vagal motoneuronal activity was still present after all movements had been prevented by curare paralysis although the frequency of the rhythm was higher than in the ventilating fish. Electrical stimulation of vagal sensory fibres had 3 effects on the ventilatory movements. (1) It evoked a reflex contraction of several gill muscles after a latency of about 11 ms. (2) It could reset the respiratory cycle because a stimulus given during expansion delayed the onset of the subsequent contraction. (3) The stimulus could entrain the rhythm if it was given continuously at a frequency close to that of ventilation. The vagal motor rhythm was disrupted by trigeminal nerve stimulation in the paralyzed fish but not if the motor rhythm was being entrained by vagal nerve stimulation. Vagal sensory activity may be important, therefore, in maintaining the stability of the generating circuits.Abbreviation LED Light emitting diode     

Mixed Signal Learning by Spike Correlation Propagation in Feedback Inhibitory Circuits

The brain can learn and detect mixed input signals masked by various types of noise, and spike-timing-dependent plasticity (STDP) is the candidate synaptic level mechanism. Because sensory inputs typically have spike correlation, and local circuits have dense feedback connections, input spikes cause the propagation of spike correlation in lateral circuits; however, it is largely unknown how this secondary correlation generated by lateral circuits influences learning processes through STDP, or whether it is beneficial to achieve efficient spike-based learning from uncertain stimuli. To explore the answers to these questions, we construct models of feedforward networks with lateral inhibitory circuits and study how propagated correlation influences STDP learning, and what kind of learning algorithm such circuits achieve. We derive analytical conditions at which neurons detect minor signals with STDP, and show that depending on the origin of the noise, different correlation timescales are useful for learning. In particular, we show that non-precise spike correlation is beneficial for learning in the presence of cross-talk noise. We also show that by considering excitatory and inhibitory STDP at lateral connections, the circuit can acquire a lateral structure optimal for signal detection. In addition, we demonstrate that the model performs blind source separation in a manner similar to the sequential sampling approximation of the Bayesian independent component analysis algorithm. Our results provide a basic understanding of STDP learning in feedback circuits by integrating analyses from both dynamical systems and information theory.     

Magnetic stimulation of the human motor cortex evokes skin sympathetic nerve activity.

Single-pulse magnetic coil stimulation (Cadwell MES 10) over the cranium induces without pain an electric pulse in the underlying cerebral cortex. Stimulation over the motor cortex can elicit a muscle twitch. In 10 subjects, we tested whether motor cortical stimulation could also elicit skin sympathetic nerve activity (SSNA; n = 8) and muscle sympathetic nerve activity (MSNA; n = 5) in the peroneal nerve. Focal motor cortical stimulation predictably elicited bursts of SSNA but not MSNA; with successive stimuli, the SSNA responses did not readily extinguish (94% of discharges to the motor cortex evoked SSNA responses) and had predictable latencies [739 +/- 33 (SE) to 895 +/- 13 ms]. The SSNA responses were similar after stimulation of dominant and nondominant sides. Focal stimulation posterior to the motor cortex elicited extinguishable SSNA responses. In three of six subjects, anterior cortical stimulation evoked SSNA responses similar to those seen with motor cortex stimulation but without detectable movement; in the other subjects, anterior stimulation evoked less SSNA discharge than that seen with motor cortex stimulation. Contrasting with motor cortical stimulation, evoked SSNA responses were more readily extinguished with 1) peripheral stimulation that directly elicited forearm muscle activation accompanied by electromyograms similar to those with motor cortical stimulation; 2) auditory stimulation by the click of the energized coil when off the head; and 3) in preliminary experiments, finger afferent stimulation sufficient to cause tingling. Our findings are consistent with the hypothesis that motor cortex stimulation can cause activation of both alpha-motoneurons and SSNA.     

Dopamine in Motor Cortex Is Necessary for Skill Learning and Synaptic Plasticity

Preliminary evidence indicates that dopamine given by mouth facilitates the learning of motor skills and improves the recovery of movement after stroke. The mechanism of these phenomena is unknown. Here, we describe a mechanism by demonstrating in rat that dopaminergic terminals and receptors in primary motor cortex (M1) enable motor skill learning and enhance M1 synaptic plasticity. Elimination of dopaminergic terminals in M1 specifically impaired motor skill acquisition, which was restored upon DA substitution. Execution of a previously acquired skill was unaffected. Reversible blockade of M1 D1 and D2 receptors temporarily impaired skill acquisition but not execution, and reduced long-term potentiation (LTP) within M1, a form of synaptic plasticity critically involved in skill learning. These findings identify a behavioral and functional role of dopaminergic signaling in M1. DA in M1 optimizes the learning of a novel motor skill.     

Nogo Receptor 1 Limits Tactile Task Performance Independent of Basal Anatomical Plasticity

The genes that govern how experience refines neural circuitry and alters synaptic structural plasticity are poorly understood. The nogo-66 receptor 1 gene (ngr1) is one candidate that may restrict the rate of learning as well as basal anatomical plasticity in adult cerebral cortex. To investigate if ngr1 limits the rate of learning we tested adult ngr1 null mice on a tactile learning task. Ngr1 mutants display greater overall performance despite a normal rate of improvement on the gap-cross assay, a whisker-dependent learning paradigm. To determine if ngr1 restricts basal anatomical plasticity in the associated sensory cortex, we repeatedly imaged dendritic spines and axonal varicosities of both constitutive and conditional adult ngr1 mutant mice in somatosensory barrel cortex for two weeks through cranial windows with two-photon chronic in vivo imaging. Neither constant nor acute deletion of ngr1 affected turnover or stability of dendritic spines or axonal boutons. The improved performance on the gap-cross task is not attributable to greater motor coordination, as ngr1 mutant mice possess a mild deficit in overall performance and a normal learning rate on the rotarod, a motor task. Mice lacking ngr1 also exhibit normal induction of tone-associated fear conditioning yet accelerated fear extinction and impaired consolidation. Thus, ngr1 alters tactile and motor task performance but does not appear to limit the rate of tactile or motor learning, nor determine the low set point for synaptic turnover in sensory cortex.