Motor learning in man: A review of functional and clinical studies

This chapter reviews results of clinical and functional imaging studies which investigated the time-course of cortical and subcortical activation during the acquisition of motor a skill. During the early phases of learning by trial and error, activation in prefrontal areas, especially in the dorsolateral prefrontal cortex, is has been reported. The role of these areas is presumably related to explicit working memory and the establishment of a novel association between visual cues and motor commands. Furthermore, motor associated areas of the right hemisphere and distributed cerebellar areas reveal strong activation during the early motor learning. Activation in superior-posterior parietal cortex presumably arises from visuospatial processes, while sensory feedback is coded in the anterior-inferior parietal cortex and the neocerebellar structures. With practice, motor associated areas of the left-hemisphere reveal increased activity. This shift to the left hemisphere has been observed regardless of the hand used during training, indicating a left-hemispheric dominance in the storage of visuomotor skills. Concerning frontal areas, learned actions of sequential character are represented in the caudal part of the supplementary motor area (SMA proper), whereas the lateral premotor cortex appears to be responsible for the coding of the association between visuo-spatial information and motor commands. Functional imaging studies which investigated the activation patterns of motor learning under implicit conditions identified for the first, a motor circuit which includes lateral premotor cortex and SMA proper of the left hemisphere and primary motor cortex, for the second, a cognitive loop which consists of basal ganglia structures of the right hemisphere. Finally, activity patterns of intermanual transfer are discussed. After right-handed training, activity in motor associated areas maintains during performance of the mirror version, but is increased during the performance of the original-oriented version with the left hand. In contrary, increased activity during the mirror reversed action, but not during the original-oriented performance of the untrained right hand is observed after left-handed training. These results indicate the transfer of acquired right-handed information which reflects the mirror symmetry of the body, whereas spatial information is mainly transferred after left-handed training. Taken together, a combined approach of clinical lesion studies and functional imaging is a promising tool for identifying the cerebral regions involved in the process of motor learning and provides insight into the mechanisms underlying the generalisation of actions.     

Role of motor cortex in coordinating multi-joint movements: is it time for a new paradigm?

Reaching movements to spatial targets require motor patterns at the shoulder to be coordinated carefully with those at the elbow to smoothly move the hand through space. While the motor cortex is involved in this volitional task, considerable debate remains about how this cortical region participates in planning and controlling movement. This article reviews two opposing interpretations of motor cortical function during multi-joint movements. On the one hand, studies performed predominantly on single-joint movement generally support the notion that motor cortical activity is intimately involved in generating motor patterns at a given joint. In contrast, studies on reaching demonstrate correlations between motor cortical activity and features of movement related to the hand, suggesting that the motor cortex may be involved in more global features of the task. Although this latter paradigm involves a multi-joint motor task in which neural activity is correlated with features of movement related to the hand, this neural activity is also correlated to other movement variables. Therefore it is difficult to assess if and how the motor cortex contributes to the coordination of motor patterns at different joints. In particular, present paradigms cannot assess whether motor cortical activity contributes to the control of one joint or multiple joints during whole-arm tasks. The final point discussed in this article is the development of a new experimental device (KINARM) that can both monitor and manipulate the mechanics of the shoulder and elbow independently during multi-joint motor tasks. It is hoped that this new device will provide a new approach for examining how the motor cortex is involved in motor coordination.     

Visuomotor transformations: early cortical mechanisms of reaching

Recent studies of visually guided reaching in monkeys support the hypothesis that the visuomotor transformations underlying arm movements to spatial targets involve a parallel mechanism that simultaneously engages functionally related frontal and parietal areas linked by reciprocal cortico-cortical connections. The neurons in these areas possess similar combinations of response properties. The multimodal combinatorial properties of these neurons and the gradient architecture of the parieto-frontal network emerge as a potential substrate to link the different sensory and motor signals that arise during reaching behavior into common hybrid reference frames. This convergent combinatorial process is evident at early stages of visual information processing in the occipito-parietal cortex, suggesting the existence of re-entrant motor influences on cortical areas once believed to have only visual functions.     

Motor Skill Learning Is Associated with Phase-Dependent Modifications in the Striatal cAMP/PKA/DARPP-32 Signaling Pathway in Rodents

Abundant evidence points to a key role of dopamine in motor skill learning, although the underlying cellular and molecular mechanisms are still poorly understood. Here, we used a skilled-reaching paradigm to first examine changes in the expression of the plasticity-related gene Arc to map activity in cortico-striatal circuitry during different phases of motor skill learning in young animals. In the early phase, Arc mRNA was significantly induced in the medial prefrontal cortex (mPFC), cingulate cortex, primary motor cortex, and striatum. In the late phase, expression of Arc did not change in most regions, except in the mPFC and dorsal striatum. In the second series of experiments, we studied the learning-induced changes in the phosphorylation state of dopamine and cAMP-regulated phosphoprotein, 32k Da (DARPP-32). Western blot analysis of the phosphorylation state of DARPP-32 and its downstream target cAMP response element-binding protein (CREB) in the striatum revealed that the early, but not late, phase of motor skill learning was associated with increased levels of phospho-Thr34-DARPP-32 and phospho-Ser133-CREB. Finally, we used the DARPP-32 knock-in mice with a point mutation in the Thr34 regulatory site (i.e., protein kinase A site) to test the significance of this pathway in motor skill learning. In accordance with our hypothesis, inhibition of DARPP-32 activity at the Thr34 regulatory site strongly attenuated the motor learning rate and skilled reaching performance of mice. These findings suggest that the cAMP/PKA/DARPP-32 signaling pathway is critically involved in the acquisition of novel motor skills, and also demonstrate a dynamic shift in the contribution of cortico-striatal circuitry during different phases of motor skill learning.     

Influence of Vibration on Motor Responses in the Upper Arm Muscles under Stationary Conditions and during Voluntary and Evoked Arm Movements under Limb Unloading Conditions

Locomotion of mammals, including humans, is based on the rhythmic activity of spinal cord circuitries. The functioning of these circuitries depends on multimodal afferent information and on supraspinal influences from the motor cortex. Using the method of transcranial magnetic stimulation (TMS) of arm muscle areas in the motor cortex, we studied the motor evoked potentials (MEP) in the upper arm muscles in stationary conditions and during voluntary and vibration-evoked arm movements. The study included 13 healthy subjects under arm and leg unloading conditions. In the first series of experiments, with motionless limbs, the effect of vibration of left upper arm muscles on motor responses in these muscles was evaluated. In the second series of experiments, MEP were compared in the same muscles during voluntary and rhythmic movements generated by left arm m. triceps brachii vibration (the right arm was stationary). Motionless left arm vibration led to an increase in MEP values in both vibrated muscle and in most of the non-vibrated muscles. For most target muscles, MEP was greater with voluntary arm movements than with vibration-evoked movements. At the same time, a similar MEP modulation in the cycle of arm movements was observed in the same upper arm muscles during both types of arm movements. TMS of the motor cortex significantly potentiated arm movements generated by vibration, but its effect on voluntary movements was weaker. These results indicate significant differences in the degree of motor cortex involvement in voluntary and evoked arm movements. We suppose that evoked arm movements are largely due to spinal rather than central mechanisms of generation of rhythmic movements.     

Comparison of neuronal response pattern in the rat somatosensory cortex during active and passive vibrissae movements

A comparative study of neuronal response in separate cortical columns of the somatosensory cortex (the barrel field area) was made in unanesthetized partially curarized white rats under various circumstances: during passive deflection of immobile vibrissa, unhindered volitional sweeping movement of the vibrissae, and during movement induced by stimulating the motor cortex and facial muscles. Differences in the response of the same neurons emerged under these different experimental situations. Different groups of neurons — responding before, during, and after volitional vibrissa movements were observed. Such response is thought to be triggered by different afferent trains reaching cortical column neurons from sources including the motor cortex, the vibrissa follicle receptors, and facial muscles.Institute of Neurocybernetics, State University, Rostov-on-Don. State University, Simferopol. Translated from Neirofiziologiya, Vol. 22, No. 2, pp. 235–242, March–April, 1990.     

FMRI supports the sensorimotor theory of motor resonance

The neural mechanisms mediating the activation of the motor system during action observation, also known as motor resonance, are of major interest to the field of motor control. It has been proposed that motor resonance develops in infants through Hebbian plasticity of pathways connecting sensory and motor regions that fire simultaneously during imitation or self movement observation. A fundamental problem when testing this theory in adults is that most experimental paradigms involve actions that have been overpracticed throughout life. Here, we directly tested the sensorimotor theory of motor resonance by creating new visuomotor representations using abstract stimuli (motor symbols) and identifying the neural networks recruited through fMRI. We predicted that the network recruited during action observation and execution would overlap with that recruited during observation of new motor symbols. Our results indicate that a network consisting of premotor and posterior parietal cortex, the supplementary motor area, the inferior frontal gyrus and cerebellum was activated both by new motor symbols and by direct observation of the corresponding action. This tight spatial overlap underscores the importance of sensorimotor learning for motor resonance and further indicates that the physical characteristics of the perceived stimulus are irrelevant to the evoked response in the observer.     

Physiological and pathological oscillatory networks in the human motor system.

Human brain functions are heavily contingent on neural interactions both at the single neuron and the neural population or system level. Accumulating evidence from neurophysiological studies strongly suggests that coupling of oscillatory neural activity provides an important mechanism to establish neural interactions. With the availability of whole-head magnetoencephalography (MEG) macroscopic oscillatory activity can be measured non-invasively from the human brain with high temporal and spatial resolution. To localise, quantify and map oscillatory activity and interactions onto individual brain anatomy we have developed the 'dynamic imaging of coherent sources' (DICS) method which allows to identify and analyse cerebral oscillatory networks from MEG recordings. Using this approach we have characterized physiological and pathological oscillatory networks in the human sensorimotor system. Coherent 8 Hz oscillations emerge from a cerebello-thalamo-premotor-motor cortical network and exert an 8 Hz oscillatory drive on the spinal motor neurons which can be observed as a physiological tremulousness of the movement termed movement discontinuities. This network represents the neurophysiological substrate of a discrete mode of motor control. In parkinsonian resting tremor we have identified an extensive cerebral network consisting of primary motor and lateral premotor cortex, supplementary motor cortex, thalamus/basal ganglia, posterior parietal cortex and secondary somatosensory cortex, which are entrained in the tremor or twice the tremor rhythm. This low frequency entrapment of motor areas likely plays an important role in the pathophysiology of parkinsonian motor symptoms. Finally, studies on patients with postural tremor in hepatic encephalopathy revealed that this type of tremor results from a pathologically slow thalamocortical and cortico-muscular coupling during isometric hold tasks. In conclusion, the analysis of oscillatory cerebral networks provides new insights into physiological mechanisms of motor control and pathophysiological mechanisms of tremor disorders.     

黑龙江省齐齐哈尔医学院第三附属医院神经内科

脑卒中后运动功能恢复的机制尚未完全阐明。研究表明中风后功能的恢复与大脑可塑性有关,本文旨在阐述近年对一侧脑缺血后双侧大脑半球的活动的研究成果。     

Sustained contraction at very low forces produces prominent supraspinal fatigue in human elbow flexor muscles.

During sustained maximal voluntary contractions (MVCs), most fatigue occurs within the muscle, but some occurs because voluntary activation of the muscle declines (central fatigue), and some of this reflects suboptimal output from the motor cortex (supraspinal fatigue). This study examines whether supraspinal fatigue occurs during a sustained submaximal contraction of 5% MVC. Eight subjects sustained an isometric elbow flexion of 5% MVC for 70 min. Brief MVCs were performed every 3 min, with stimulation of the motor point, motor cortex, and brachial plexus. Perceived effort and pain, elbow flexion torque, and surface EMGs from biceps and brachioradialis were recorded. During the sustained 5% contraction, perceived effort increased from 0.5 to 3.9 (out of 10), and elbow flexor EMG increased steadily by approximately 60-80%. Torque during brief MVCs fell to 72% of control values, while both the resting twitch and EMG declined progressively. Thus the sustained weak contraction caused fatigue, some of which was due to peripheral mechanisms. Voluntary activation measured by motor point and motor cortex stimulation methods fell to 90% and 80%, respectively. Thus some of the fatigue was central. Calculations based on the fall in voluntary activation measured with cortical stimulation indicate that about two-thirds of the fatigue was due to supraspinal mechanisms. Therefore, sustained performance of a very low-force contraction produces a progressive inability to drive the motor cortex optimally during brief MVCs. The effect of central fatigue on performance of the weak contraction is less clear, but it may contribute to the increase in perceived effort.     

Motor learning with unstable neural representations

It is often assumed that learning takes place by changing an otherwise stable neural representation. To test this assumption, we studied changes in the directional tuning of primate motor cortical neurons during reaching movements performed in familiar and novel environments. During the familiar task, tuning curves exhibited slow random drift. During learning of the novel task, random drift was accompanied by systematic shifts of tuning curves. Our analysis suggests that motor learning is based on a surprisingly unstable neural representation. To explain these results, we propose that motor cortex is a redundant neural network, i.e., any single behavior can be realized by multiple configurations of synaptic strengths. We further hypothesize that synaptic modifications underlying learning contain a random component, which causes wandering among synaptic configurations with equivalent behaviors but different neural representations. We use a simple model to explore the implications of these assumptions.     

Stroke rehabilitation reaches a threshold

Motor training with the upper limb affected by stroke partially reverses the loss of cortical representation after lesion and has been proposed to increase spontaneous arm use. Moreover, repeated attempts to use the affected hand in daily activities create a form of practice that can potentially lead to further improvement in motor performance. We thus hypothesized that if motor retraining after stroke increases spontaneous arm use sufficiently, then the patient will enter a virtuous circle in which spontaneous arm use and motor performance reinforce each other. In contrast, if the dose of therapy is not sufficient to bring spontaneous use above threshold, then performance will not increase and the patient will further develop compensatory strategies with the less affected hand. To refine this hypothesis, we developed a computational model of bilateral hand use in arm reaching to study the interactions between adaptive decision making and motor relearning after motor cortex lesion. The model contains a left and a right motor cortex, each controlling the opposite arm, and a single action choice module. The action choice module learns, via reinforcement learning, the value of using each arm for reaching in specific directions. Each motor cortex uses a neural population code to specify the initial direction along which the contralateral hand moves towards a target. The motor cortex learns to minimize directional errors and to maximize neuronal activity for each movement. The derived learning rule accounts for the reversal of the loss of cortical representation after rehabilitation and the increase of this loss after stroke with insufficient rehabilitation. Further, our model exhibits nonlinear and bistable behavior: if natural recovery, motor training, or both, brings performance above a certain threshold, then training can be stopped, as the repeated spontaneous arm use provides a form of motor learning that further bootstraps performance and spontaneous use. Below this threshold, motor training is "in vain": there is little spontaneous arm use after training, the model exhibits learned nonuse, and compensatory movements with the less affected hand are reinforced. By exploring the nonlinear dynamics of stroke recovery using a biologically plausible neural model that accounts for reversal of the loss of motor cortex representation following rehabilitation or the lack thereof, respectively, we can explain previously hard to reconcile data on spontaneous arm use in stroke recovery. Further, our threshold prediction could be tested with an adaptive train-wait-train paradigm: if spontaneous arm use has increased in the "wait" period, then the threshold has been reached, and rehabilitation can be stopped. If spontaneous arm use is still low or has decreased, then another bout of rehabilitation is to be provided.     

Effect of fenamin and haloperidol on conditioned activity of neurons of the motor cortex and striopallidal system

The activity of neurones in the motor cortex, caudate nucleus, putamen and globus pallidus was studied during elaboration of motor conditioned reflexes to time in rabbits, treated with 1-amphetamine and haloperidol. Mechanisms of reproduction of cells trace activity in the reflex to time at the omission of trials, reacted to 1-amphetamine by increasing the intensity of reactions in the motor cortex and inactivation in putamen cells. The curve of dynamics of intensity changes of trace discharges in the course of a series of trials omissions remained unaltered only in motor cortex; in the other structures it significantly differed from the norm of intact animals. Haloperidol depressed the mechanisms of reproduction of trace reactions of the globus pallidus cells, and made them almost fully inactive in the motor cortex; the putamen neurones reacted to haloperidol by an increase of trace reactions intensity. Against the background of the animal chronic 1-amphetamine intoxication, haloperidol normalized the dynamics and intensity of trace activity. "Therapeutic" effect of haloperidol was most distinctly expressed in the motor cortex and putamen cells, less--in the caudate nucleus and was completely absent in the globus pallidus.     

Dopamine Promotes Motor Cortex Plasticity and Motor Skill Learning via PLC Activation

Dopaminergic neurons in the ventral tegmental area, the major midbrain nucleus projecting to the motor cortex, play a key role in motor skill learning and motor cortex synaptic plasticity. Dopamine D1 and D2 receptor antagonists exert parallel effects in the motor system: they impair motor skill learning and reduce long-term potentiation. Traditionally, D1 and D2 receptor modulate adenylyl cyclase activity and cyclic adenosine monophosphate accumulation in opposite directions via different G-proteins and bidirectionally modulate protein kinase A (PKA), leading to distinct physiological and behavioral effects. Here we show that D1 and D2 receptor activity influences motor skill acquisition and long term synaptic potentiation via phospholipase C (PLC) activation in rat primary motor cortex. Learning a new forelimb reaching task is severely impaired in the presence of PLC, but not PKA-inhibitor. Similarly, long term potentiation in motor cortex, a mechanism involved in motor skill learning, is reduced when PLC is inhibited but remains unaffected by the PKA inhibitor. Skill learning deficits and reduced synaptic plasticity caused by dopamine antagonists are prevented by co-administration of a PLC agonist. These results provide evidence for a role of intracellular PLC signaling in motor skill learning and associated cortical synaptic plasticity, challenging the traditional view of bidirectional modulation of PKA by D1 and D2 receptors. These findings reveal a novel and important action of dopamine in motor cortex that might be a future target for selective therapeutic interventions to support learning and recovery of movement resulting from injury and disease.     

Neural basis of learning new movements: evolution of classical concepts

According to classical consepts, the role of the motor cortex in performance of skilled movements of distal parts of extremities is confined to control of appropriate motoneurons by the "point-to-point" principle. However, much evidence of plasticity of the motor cortex and its active role in motor learning appeared in last decade. Fos-gene expression in the motor cortex was found to accompany learning a skill. Strengthening of horizontal pathways in layers II-III was revealed, and cholinergic input to tese layers was found to be important. The imaging data show that activity of the motor cortex increases during motor practice as well. This raises the question of specificity of the motor cortex in the motor learning per se. During acquisition of new movements some previously used synergies prevent the necessary coordination from being learned, so they must be suppressed in the process of motor learning. Investigations of central mechanisms of coordination interference in humans are still at the beginning. However, there are some animal models of reorganization and suppression of interfering synergies. The reorganization and suppression of coordination preventing realization of a new movement is shown to be a specific function of the motor cortex. After automation of new synergies the cortical control is still present, as distinct from the learned movements, which do not require suppression of interfering synergies. However, it does not mean that the conscious control of the performance is still present.     

An approach to localizing corneal pain representation in human primary somatosensory cortex

The cornea has been a focus of animal electrophysiological research for decades, but little is known regarding its cortical representation in the human brain. This study attempts to localize the somatotopic representation of the cornea to painful stimuli in human primary somatosensory cortex using functional magnetic resonance imaging (fMRI). In this case study, a subject was imaged at 3T while bright light was presented in a block-design, which either produced pain and blinking (during photophobia) or blinking alone (after recovery from photophobia). Pain and blinking produced precisely localized activations in primary somatosensory cortex and primary motor cortex. These results indicate that noxious stimulation of the cornea can produce somatotopic activation in primary somatosensory cortex. This finding opens future avenues of research to evaluate the relationship between corneal pain and central brain mechanisms relating to the development of chronic pain conditions, such as dry eye-like symptoms.     

Blinking suppresses the neural response to unchanging retinal stimulation

Blinks profoundly interrupt visual input but are rarely noticed, perhaps because of blink suppression, a visual-sensitivity loss that begins immediately prior to blink onset. Blink suppression is thought to result from an extra-retinal signal that is associated with the blink motor command and may act to attenuate the sensory consequences of the motor action. However, the neural mechanisms underlying this phenomenon remain unclear. They are challenging to study because any brain-activity changes resulting from an extra-retinal signal associated with the blink motor command are potentially masked by profound neural-activity changes caused by the retinal-illumination reduction that results from occlusion of the pupil by the eyelid. Here, we distinguished direct top-down effects of blink-associated motor signals on cortical activity from purely mechanical or optical effects of blinking on visual input by combining pupil-independent retinal stimulation with functional MRI (fMRI) in humans. Even though retinal illumination was kept constant during blinks, we found that blinking nevertheless suppressed activity in visual cortex and in areas of parietal and prefrontal cortex previously associated with awareness of environmental change. Our findings demonstrate active top-down modulation of visual processing during blinking, suggesting a possible mechanism by which blinks go unnoticed.     

Learning with slight forgetting optimizes sensorimotor transformation in redundant motor systems

Recent theoretical studies have proposed that the redundant motor system in humans achieves well-organized stereotypical movements by minimizing motor effort cost and motor error. However, it is unclear how this optimization process is implemented in the brain, presumably because conventional schemes have assumed a priori that the brain somehow constructs the optimal motor command, and largely ignored the underlying trial-by-trial learning process. In contrast, recent studies focusing on the trial-by-trial modification of motor commands based on error information suggested that forgetting (i.e., memory decay), which is usually considered as an inconvenient factor in motor learning, plays an important role in minimizing the motor effort cost. Here, we examine whether trial-by-trial error-feedback learning with slight forgetting could minimize the motor effort and error in a highly redundant neural network for sensorimotor transformation and whether it could predict the stereotypical activation patterns observed in primary motor cortex (M1) neurons. First, using a simple linear neural network model, we theoretically demonstrated that: 1) this algorithm consistently leads the neural network to converge at a unique optimal state; 2) the biomechanical properties of the musculoskeletal system necessarily determine the distribution of the preferred directions (PD; the direction in which the neuron is maximally active) of M1 neurons; and 3) the bias of the PDs is steadily formed during the minimization of the motor effort. Furthermore, using a non-linear network model with realistic musculoskeletal data, we demonstrated numerically that this algorithm could consistently reproduce the PD distribution observed in various motor tasks, including two-dimensional isometric torque production, two-dimensional reaching, and even three-dimensional reaching tasks. These results may suggest that slight forgetting in the sensorimotor transformation network is responsible for solving the redundancy problem in motor control.     

Trial-to-Trial Reoptimization of Motor Behavior Due to Changes in Task Demands Is Limited

Each task requires a specific motor behavior that is tuned to task demands. For instance, writing requires a lot of accuracy while clapping does not. It is known that the brain adjusts the motor behavior to different task demands as predicted by optimal control theory. In this study, the mechanism of this reoptimization process is investigated by varying the accuracy demands of a reaching task. In this task, the width of the reaching target (0.5 or 8 cm) was varied either on a trial-to-trial basis (random schedule) or in blocks (blocked schedule). On some trials, the hand of the subjects was clamped to a rectilinear trajectory that ended 2 cm on the left or right of the target center. The rejection of this perturbation largely varied with target width in the blocked schedule but not in the random schedule. That is, subjects exhibited different motor behavior in the different schedules despite identical accuracy demands. Therefore, while reoptimization has been considered immediate and automatic, the differences in motor behavior observed across schedules suggest that the reoptimization of the motor behavior is neither happening on a trial-by-trial basis nor obligatory. The absence of trial-to-trial mechanisms, the inability of the brain to adapt to two conflicting task demands and the existence of a switching cost are discussed as possible sources of the non-optimality of motor behavior during the random schedule.