Motor training promotes both synaptic and intrinsic plasticity of layer V pyramidal neurons in the primary motor cortex.

Layer V neurons in the primary motor cortex (M1) are important for motor skill learning. Since pretreatment of either CNQX or APV in rat M1 layer V impaired rotor rod learning, we analysed training-induced synaptic plasticity by whole-cell patch-clamp technique in acute brain slices. Rats trained for 1 day showed a decrease in small inhibitory postsynaptic current (mIPSC) frequency and an increase in the paired-pulse ratio of evoked IPSCs, suggesting a transient decrease in presynaptic GABA release in the early phase. Rats trained for 2 days showed an increase in miniature excitatory postsynaptic current (mEPSC) amplitudes/frequency and elevated AMPA/NMDA ratios, suggesting a long-term strengthening of AMPA receptor-mediated excitatory synapses. Importantly, rotor rod performance in trained rats was correlated with the mean mEPSC amplitude and the frequency obtained from that animal. In current-clamp analysis, 1-day-trained rats transiently decreased the current-induced firing rate, while 2-day-trained rats returned to pre-training levels, suggesting dynamic changes in intrinsic properties. Furthermore, western blot analysis of layer V detected decreased phosphorylation of Ser408-409 in GABAA receptor ß3 subunits in 1-day-trained rats, and increased phosphorylation of Ser831 in AMPA receptor GluA1 subunits in 2-day-trained rats. Finally, live-imaging analysis of Thy1-YFP transgenic mice showed that the training rapidly recruited a substantial number of spines for long-term plasticity in M1 layer V neurons. Taken together, these results indicate that motor training induces complex and diverse plasticity in M1 layer V pyramidal neurons. KEY POINTS: Here we examined motor training-induced synaptic and intrinsic plasticity of layer V pyramidal neurons in the primary motor cortex. The training reduced presynaptic GABA release in the early phase, but strengthened AMPA receptor-mediated excitatory synapses in the later phase: acquired motor performance after training correlated with the strength of excitatory synapses rather than inhibitory synapses. As to the intrinsic property, the training transiently decreased the firing rate in the early phase, but returned to pre-training levels in the later phase. Western blot analysis detected decreased phosphorylation of Ser408-409 in GABAA receptor ß3 subunits in the acute phase, and increased phosphorylation of Ser831 in AMPA receptor GluA1 subunits in the later phase. Live-imaging analysis of Thy1-YFP transgenic mice showed rapid and long-term spine plasticity in M1 layer V neurons, suggesting training-induced increases in self-entropy per spine.

Coupling between motor cortex and striatum increases during sleep over long-term skill learning.

The strength of cortical connectivity to the striatum influences the balance between behavioral variability and stability. Learning to consistently produce a skilled action requires plasticity in corticostriatal connectivity associated with repeated training of the action. However, it remains unknown whether such corticostriatal plasticity occurs during training itself or 'offline' during time away from training, such as sleep. Here, we monitor the corticostriatal network throughout long-term skill learning in rats and find that non-rapid-eye-movement (NREM) sleep is a relevant period for corticostriatal plasticity. We first show that the offline activation of striatal NMDA receptors is required for skill learning. We then show that corticostriatal functional connectivity increases offline, coupled to emerging consistent skilled movements, and coupled cross-area neural dynamics. We then identify NREM sleep spindles as uniquely poised to mediate corticostriatal plasticity, through interactions with slow oscillations. Our results provide evidence that sleep shapes cross-area coupling required for skill learning.

The Effect of Cerebellar Transcranial Direct Current Stimulation on Motor Learning: A Systematic Review of Randomized Controlled Trials.

Background: Cerebellar transcranial direct current stimulation (ctDCS) appears to modulate motor performance in both adaptation and motor skill tasks; however, whether the gains are long-lasting is unclear. Objectives: This systematic review aims to evaluate the effect of ctDCS with respect to different time scales of motor learning. Methods: Ten electronic databases (CINAHL, MEDLINE, SPORT Discus, Scopus, Web of Science, Cochrane via OVID, Evidence-Based Reviews (EBM) via OVID, AMED: Allied and Complementary Medicine, PsycINFO, and PEDro) were systematically searched. Studies evaluating the effect of ctDCS compared to sham ctDCS on motor learning in healthy individuals were selected and reviewed. Two authors independently reviewed the quality of the included studies using the revised Cochrane's risk-of-bias tool. The results were extracted with respect to the time scale in which changes in motor performance were evaluated. Results: Seventeen randomized controlled trials met the eligibility criteria of which 65% of the studies had a "high" risk-of-bias, and 35% had "some concerns." These studies included data from 629 healthy participants. Of the studies that evaluated the effect of anodal ctDCS during and immediately after the stimulation, four found enhanced, three found impaired, and ten found no effect on gains in motor performance. Of the studies that evaluated the effect of anodal ctDCS after a break of 24 h or more, seven found enhanced, two found impaired, and one found no effect on gains in motor performance. Of the studies that evaluated the effect of cathodal ctDCS across a range of time scales, five found impaired, one found enhanced, and five found no effect on gains in motor performance. Conclusions: In healthy individuals, anodal ctDCS appears to improve short to longer-term motor skill learning, whereas it appears to have no effect on gains in motor performance during and immediate after the stimulation. ctDCS may have potential to improve motor performance beyond the training period. The challenge of the motor task and its characteristics, and the stimulation parameters are likely to influence the effect of ctDCS on motor learning.

Muscleless motor synergies and actions without movements: From motor neuroscience to cognitive robotics.

Emerging trends in neurosciences are providing converging evidence that cortical networks in predominantly motor areas are activated in several contexts related to 'action' that do not cause any overt movement. Indeed for any complex body, human or embodied robot inhabiting unstructured environments, the dual processes of shaping motor output during action execution and providing the self with information related to feasibility, consequence and understanding of potential actions (of oneself/others) must seamlessly alternate during goal-oriented behaviors, social interactions. While prominent approaches like Optimal Control, Active Inference converge on the role of forward models, they diverge on the underlying computational basis. In this context, revisiting older ideas from motor control like the Equilibrium Point Hypothesis and synergy formation, this article offers an alternative perspective emphasizing the functional role of a 'plastic, configurable' internal representation of the body (body-schema) as a critical link enabling the seamless continuum between motor control and imagery. With the central proposition that both "real and imagined" actions are consequences of an internal simulation process achieved though passive goal-oriented animation of the body schema, the computational/neural basis of muscleless motor synergies (and ensuing simulated actions without movements) is explored. The rationale behind this perspective is articulated in the context of several interdisciplinary studies in motor neurosciences (for example, intracranial depth recordings from the parietal cortex, FMRI studies highlighting a shared cortical basis for action 'execution, imagination and understanding'), animal cognition (in particular, tool-use and neuro-rehabilitation experiments, revealing how coordinated tools are incorporated as an extension to the body schema) and pertinent challenges towards building cognitive robots that can seamlessly "act, interact, anticipate and understand" in unstructured natural living spaces.

Higher-order Brain Areas Associated with Real-time Functional MRI Neurofeedback Training of the Somato-motor Cortex.

Neurofeedback (NFB) allows subjects to learn self-regulation of neuronal brain activation based on information about the ongoing activation. The implementation of real-time functional magnetic resonance imaging (rt-fMRI) for NFB training now facilitates the investigation into underlying processes. Our study involved 16 control and 16 training right-handed subjects, the latter performing an extensive rt-fMRI NFB training using motor imagery. A previous analysis focused on the targeted primary somato-motor cortex (SMC). The present study extends the analysis to the supplementary motor area (SMA), the next higher brain area within the hierarchy of the motor system. We also examined transfer-related functional connectivity using a whole-volume psycho-physiological interaction (PPI) analysis to reveal brain areas associated with learning. The ROI analysis of the pre- and post-training fMRI data for motor imagery without NFB (transfer) resulted in a significant training-specific increase in the SMA. It could also be shown that the contralateral SMA exhibited a larger increase than the ipsilateral SMA in the training and the transfer runs, and that the right-hand training elicited a larger increase in the transfer runs than the left-hand training. The PPI analysis revealed a training-specific increase in transfer-related functional connectivity between the left SMA and frontal areas as well as the anterior midcingulate cortex (aMCC) for right- and left-hand trainings. Moreover, the transfer success was related with training-specific increase in functional connectivity between the left SMA and the target area SMC. Our study demonstrates that NFB training increases functional connectivity with non-targeted brain areas. These are associated with the training strategy (i.e., SMA) as well as with learning the NFB skill (i.e., aMCC and frontal areas). This detailed description of both the system to be trained and the areas involved in learning can provide valuable information for further optimization of NFB trainings.

A proof-of-principle simulation for closed-loop control based on preexisting experimental thalamic DBS-enhanced instrumental learning.

Deep brain stimulation (DBS) has been applied as an effective therapy for treating Parkinson's disease or essential tremor. Several open-loop DBS control strategies have been developed for clinical experiments, but they are limited by short battery life and inefficient therapy. Therefore, many closed-loop DBS control systems have been designed to tackle these problems by automatically adjusting the stimulation parameters via feedback from neural signals, which has been reported to reduce the power consumption. However, when the association between the biomarkers of the model and stimulation is unclear, it is difficult to develop an optimal control scheme for other DBS applications, i.e., DBS-enhanced instrumental learning. Furthermore, few studies have investigated the effect of closed-loop DBS control for cognition function, such as instrumental skill learning, and have been implemented in simulation environments. In this paper, we proposed a proof-of-principle design for a closed-loop DBS system, cognitive-enhancing DBS (ceDBS), which enhanced skill learning based on in vivo experimental data. The ceDBS acquired local field potential (LFP) signal from the thalamic central lateral (CL) nuclei of animals through a neural signal processing system. A strong coupling of the theta oscillation (4-7 Hz) and the learning period was found in the water reward-related lever-pressing learning task. Therefore, the theta-band power ratio, which was the averaged theta band to averaged total band (1-55 Hz) power ratio, could be used as a physiological marker for enhancement of instrumental skill learning. The on-line extraction of the theta-band power ratio was implemented on a field-programmable gate array (FPGA). An autoregressive with exogenous inputs (ARX)-based predictor was designed to construct a CL-thalamic DBS model and forecast the future physiological marker according to the past physiological marker and applied DBS. The prediction could further assist the design of a closed-loop DBS controller. A DBS controller based on a fuzzy expert system was devised to automatically control DBS according to the predicted physiological marker via a set of rules. The simulated experimental results demonstrate that the ceDBS based on the closed-loop control architecture not only reduced power consumption using the predictive physiological marker, but also achieved a desired level of physiological marker through the DBS controller.

Enduring Poststroke Motor Functional Improvements by a Well-Timed Combination of Motor Rehabilitative Training and Cortical Stimulation in Rats.

BACKGROUND: In animal stroke models, peri-infarct cortical stimulation (CS) combined with rehabilitative reach training (RT) enhances motor functional outcome and cortical reorganization, compared with RT alone. It was unknown whether the effects of CS + RT (a) persist long after treatment, (b) can be enhanced by forcing greater use of the paretic limb, and (C) vary with treatment onset time. OBJECTIVE: To test the endurance, time sensitivity, and the potential for augmentation by forced forelimb use of CS + RT treatment effects following ischemic stroke. METHODS: Adult rats that were proficient in skilled reaching received unilateral ischemic motor cortical lesions. RT was delivered for 3 weeks alone or concurrently with 100-Hz cathodal epidural CS, delivered at 50% of movement thresholds. In study 1, this treatment was initiated at 14 days postinfarct, with some subgroups receiving an overlapping period of continuous constraint of the nonparetic forelimb to force use of the paretic limb. The function of the paretic limb was assessed weekly for 9 to 10 months posttreatment. In study 2, rats underwent CS, RT, and the combination during the chronic postinfarct period. RESULTS: Early onset CS + RT resulted in greater functional improvements than RT alone. The CS-related gains persisted for 9 to 10 months posttreatment and were not significantly influenced by forced use of the paretic limb. When treatment onset was delayed until 3 months post-infarct, RT alone improved function, but CS + RT was no more effective than RT alone. CONCLUSION: CS can enhance the persistence, as well as the magnitude of RT-driven functional improvements, but its effectiveness in doing so may vary with time postinfarct.

Towards the integration of mental practice in rehabilitation programs. A critical review.

Many clinical studies have investigated the use of mental practice (MP) through motor imagery (MI) to enhance functional recovery of patients with diverse physical disabilities. Although beneficial effects have been generally reported for training motor functions in persons with chronic stroke (e.g., reaching, writing, walking), attempts to integrate MP within rehabilitation programs have been met with mitigated results. These findings have stirred further questioning about the value of MP in neurological rehabilitation. In fact, despite abundant systematic reviews, which customarily focused on the methodological merits of selected studies, several questions about factors underlying observed effects remain to be addressed. This review discusses these issues in an attempt to identify factors likely to hamper the integration of MP within rehabilitation programs. First, the rationale underlying the use of MP for training motor function is briefly reviewed. Second, three modes of MI delivery are proposed based on the analysis of the research protocols from 27 studies in persons with stroke and Parkinson's disease. Third, for each mode of MI delivery, a general description of MI training is provided. Fourth, the review discusses factors influencing MI training outcomes such as: the adherence to MI training, the amount of training and the interaction between physical and mental rehearsal; the use of relaxation, the selection of reliable, valid and sensitive outcome measures, the heterogeneity of the patient groups, the selection of patients and the mental rehearsal procedures. To conclude, the review proposes a framework for integrating MP in rehabilitation programs and suggests research targets for steering the implementation of MP in the early stages of the rehabilitation process. The challenge has now shifted towards the demonstration that MI training can enhance the effects of regular therapy in persons with subacute stroke during the period of spontaneous recovery.