Article

Functional Reorganization of the Rat Motor Cortex Following Motor Skill Learning

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  • University of Kansas Medical Center, Kansas City, United States
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Abstract

Functional reorganization of the rat motor cortex following motor skill learning. J. Neurophysiol. 80: 3321-3325, 1998. Adult rats were allocated to either a skilled or unskilled reaching condition (SRC and URC, respectively). SRC animals were trained for 10 days on a skilled reaching task while URC animals were trained on a simple bar pressing task. After training, microelectrode stimulation was used to derive high resolution maps of the forelimb and hindlimb representations within the motor cortex. In comparison with URC animals, SRC animals exhibited a significant increase in mean area of the wrist and digit representations but a decrease in elbow/shoulder representation within the caudal forelimb area. No between-group differences in areal representation were found in either the hindlimb or rostral forelimb areas. These results demonstrate that motor skill learning is associated with a reorganization of movement representations within the rodent motor cortex.

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... In contrast, how many times tasks are practiced is an important driver of recovery of motor function. Thankfully, the number of repetitions required for this recovery has been reported both in animals and humans, and it ranges between 289 and 1000 repetitions per day [28][29][30][31][32][33][34][35]. In particular, the studies on upper limb showed that using number of repetitions of task practice as a measure of intensity is feasible and effective at improving outcomes such as motor function, real-world arm use, and upper limb self-efficacy [32][33][34]. ...
... However, group 1 performed each of the tasks 40 times per session (altogether 200 repetitions), three sessions (morning, afternoon, and evening) per day (altogether 600 repetitions), five days per week, and with constraint applied only during practice sessions for four consecutive weeks. 600 repetitions were used because results of previous studies showed that for motor recovery to be achieved, task repetitions in the range of 300 to 800 per day is required [28,29,32]. On the other hand, group 2 performed modified CIMT consisting 2 ...
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Background. Constraint-induced movement therapy (CIMT) is used for the rehabilitation of motor function after stroke. Objectives. The aim of this study was to compare the effects of lower limb CIMT that uses number of repetition of tasks with the one that uses number of hours of practice. Method. The study was a randomized clinical trial approved by the Ethics Committee of Kano State Ministry of Health. Fifty-eight people with stroke participated in the study. Groups 1 and 2 performed daily 600 repetitions and 3 hours of task practice, respectively, 5 times weekly for 4 weeks. Motor impairment (primary outcome), balance, functional mobility, knee extensor spasticity, walking speed and endurance, and exertion before and after commencement of activities were assessed at baseline and postintervention. The data was analyzed using Friedmann and Mann- Whitney U tests. Result. The results showed that there was only significant difference (p < 0:05) in knee extensor spasticity (group 1 (median = 0(0), mean rank = 27:50); group 2 (median = 0(0), mean rank = 31:64)), exertion before commencement of activities (group 1 (median = 0(0.5), mean rank = 21:90); group 2 (median = 1(0.5), mean rank = 37:64)), and exertion after commencement of activities (group 1 (median = 1(1), mean rank = 20:07); group 2 (median = 1(0), mean rank = 39:61) postintervention in favour of the experimental group (group 1)). Conclusion. The group 1 protocol is more effective at improving outcomes after stroke.
... Topographically organized motor cortex consists of local and corticofugal excitatory projection neurons as well as inhibitory interneurons that delineate region boundaries and modulate the firing of pyramidal neuron ensembles (Tanaka, Tanaka et al. 2011, Kaneko 2013. Disruption of the excitatory/inhibitory balance by injection of GABA agonists shifts the topographic boundaries of motor representations that are shaped by development and refined during motor learning (Jacobs and Donoghue 1991, Galea and Darian-Smith 1995, Kleim, Barbay et al. 1998, Young, Vuong et al. 2012. Motor learning depends on the plasticity of motor networks as attenuation of cortical plasticity mechanisms impairs skilled task acquisition (Li and Hollis 2017). ...
... Microstimulation and optogenetic mapping have demonstrated strong distal motor (wrist and digit) representations in CFA, with RFA largely evoking wrist and elbow movements (Ramanathan, Conner et al. 2006, Tennant, Adkins et al. 2011, Hollis II, Ishiko et al. 2016. CFA exhibits extensive remapping with skilled behavioral training whereas RFA does not show such changes (Kleim, Barbay et al. 1998). Indeed, silencing RFA shows only minimal impairments on a directional joystick task (Bollu 2018). ...
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Hand and arm manual dexterity is a hallmark of humans and non-human primates. While rodents are less dexterous than primates, they provide powerful models for testing neural circuit function in behavioral output, including dexterous behaviors. In rodents, the single pellet reach task has been used extensively to study both dexterous forelimb motor learning as well as recovery from injury; however, mice exhibit high variability in task acquisition in comparison to rats and a significant percentage fail to learn the task. We have created a recessed version of the task that requires greater dexterity. This subtle modification increases both task difficulty as well as the proportion of mice that show an improvement with training. Furthermore, motor cortex inactivation shows a greater effect on the execution of the recessed forelimb reach task, with distinct effects on reach targeting vs grasping components depending on the timing of inhibitory activation. Kinematic analysis revealed differences in reach targeting upon transient cortical inhibition prior to reach onset. In summary, the recessed single pellet reach task provides a robust assessment of forelimb dexterity in mice and a tool for studying skilled motor acquisition and execution.
... The location of the RFA (premotor cortex in rats) was determined using standard ICMS protocols (Kleim et al. 1998). Upon completion of the craniectomy and durectomy, a picture of the vascular pattern of the cortical surface was taken and uploaded to a graphics program (Canvas GFX, Inc., Plantation, FL, USA), and a 250 μm grid was overlaid onto the image. ...
... The current was increased until visible movement around a joint was observed, up to 80 μA. The RFA was defined by forelimb motor responses bordered caudally by neck and trunk responses and medially by face and jaw movements (Kleim et al. 1998). The forelimb sensory fields in S1 were identified with multiunit recordings. ...
Article
As our understanding of volitional motor function increases, it is clear that complex movements are the result of the interactions of multiple cortical regions rather than just the output properties of primary motor cortex. However, our understanding of the interactions among these regions is limited. In this study, we used the activity-dependent stimulation (ADS) technique to determine the short/long-term effects on network activity and neuroplasticity of intracortical connections. ADS uses the intrinsic neural activity of one region to trigger stimulations in a separate region of the brain and can manipulate neuronal connectivity in vivo. Our aim was to compare single-unit neuronal activity within premotor cortex (rostral forelimb area, [RFA] in rats) in response to ADS (triggered from RFA) and randomly-generated stimulation in the somatosensory area (S1) within single sessions and across 21 consecutive days of stimulation. We examined firing rate and correlation between spikes and stimuli in chronically-implanted healthy ambulatory rats during spontaneous and evoked activity. At the end of the treatment, we evaluated changes of synaptophysin expression. Our results demonstrated the ability of ADS to modulate RFA firing properties and to promote synaptogenesis in S1, strengthening the idea that this Hebbian-inspired protocol can be used to modulate cortical connectivity.
... Participants Can Accomplish a Task but how They Accomplish it As stated in Krakauer and Carmichael (2017)'s exceptional book "Broken Movement, " most motor learning research in stroke has been performed under the assumption that movement practice will inherently lead to improvements in impairment (Krakauer, 2006;Krakauer and Carmichael, 2017). Under this assumption, researchers argue that task-specific practice is always associated with positive neuroplasticity such as cortical reorganization and reweighting of the neural mechanisms that mediate the control of movement (Kleim et al., 1998;Liepert et al., 2000). The idea that practiced movements will inherently lead to positive changes at the level of central nervous system is often referred to as a bottomup approach: can repeated practice with movement patterns that resemble those before stroke lead to re-learning of these patterns? ...
... Additionally, external guidance can engage the visuomotor network (Archer et al., 2018) and the cerebellum (Doya, 2000;Archer et al., 2018), and supplement impaired somatosensation post-stroke (Tate and Milner, 2010). The engagement of these neural pathways may lead to recovery-supportive cortical reorganization (Hamdy et al., 1998;Kleim et al., 1998;Liepert et al., 2000). However, an overreliance on these forms of external guidance can develop with time and thereby shift an intervention to a bottomup approach, especially if the participant's focus shifts from how the movement is performed to simply goal achievement, be it hitting a target, or completing one of hundreds of repetitions. ...
Article
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Stroke continues to be a leading cause of disability. Basic neurorehabilitation research is necessary to inform the neuropathophysiology of impaired motor control, and to develop targeted interventions with potential to remediate disability post-stroke. Despite knowledge gained from basic research studies, the effectiveness of research-based interventions for reducing motor impairment has been no greater than standard of practice interventions. In this perspective, we offer suggestions for overcoming translational barriers integral to experimental design, to augment traditional protocols, and re-route the rehabilitation trajectory toward recovery and away from compensation. First, we suggest that researchers consider modifying task practice schedules to focus on key aspects of movement quality, while minimizing the appearance of compensatory behaviors. Second, we suggest that researchers supplement primary outcome measures with secondary measures that capture emerging maladaptive compensations at other segments or joints. Third, we offer suggestions about how to maximize participant engagement, self-direction, and motivation, by embedding the task into a meaningful context, a strategy more likely to enable goal-action coupling, associated with improved neuro-motor control and learning. Finally, we remind the reader that motor impairment post-stroke is a multidimensional problem that involves central and peripheral sensorimotor systems, likely influenced by chronicity of stroke. Thus, stroke chronicity should be given special consideration for both participant recruitment and subsequent data analyses. We hope that future research endeavors will consider these suggestions in the design of the next generation of intervention studies in neurorehabilitation, to improve translation of research advances to improved participation and quality of life for stroke survivors.
... Cortical lesion studies have revealed the capacity of subcortical structures to direct a large repertoire of movements, particularly "innate" movements that don't require dexterous limb motion [1,2,3,4]. On the other hand, however, motor cortex is also known to play a major role in both the acquisition and control of motor behaviors such as task-specific limb movements in both primates [5,6,7,8,9] and rodents [10,11,12,13]. However, the precise roles and interactions of cortical and subcortical brain areas in controlling movement during skill learning have not been entirely determined. ...
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Sparse, sequential patterns of neural activity have been observed in numerous brain areas during time-keeping and motor sequence tasks. Inspired by such observations, we construct a model of the striatum, an all-inhibitory circuit where sequential activity patterns are prominent, addressing the following key challenges: (i) obtaining control over temporal rescaling of the sequence speed, with the ability to generalize to new speeds; (ii) facilitating flexible expression of distinct sequences via selective activation, concatenation, and recycling of specific subsequences; and (iii) enabling the biologically plausible learning of sequences, consistent with the decoupling of learning and execution suggested by lesion studies showing that cortical circuits are necessary for learning, but that subcortical circuits are sufficient to drive learned behaviors. The same mechanisms that we describe can also be applied to circuits with both excitatory and inhibitory populations, and hence may underlie general features of sequential neural activity pattern generation in the brain.
... Animal studies of stroke rehabilitation have demonstrated motor skill recovery that is substantially better than what is typically seen in humans (3,(7)(8)(9). Although many factors contribute to this phenomenon, the dose of practice implemented is a critical difference between neurologic rehabilitation in animal models vs. that in humans (3)(4)(5). ...
Article
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Standard dosages of motor practice in clinical physical rehabilitation are insufficient to optimize motor learning, particularly for older patients who often learn at a slower rate than younger patients. Personalized practice dosing (i.e., practicing a task to or beyond one's plateau in performance) may provide a clinically feasible method for determining a dose of practice that is both standardized and individualized, and may improve motor learning. The purpose of this study was to investigate whether personalized practice dosages [ practice to plateau (PtP) and overpractice (OVP)] improve retention and transfer of a motor task, compared to low dose [LD] practice that mimics standard clinical dosages. In this pilot randomized controlled trial (NCT02898701, ClinicalTrials.gov ), community-dwelling older adults ( n = 41, 25 female, mean age 68.9 years) with a range of balance ability performed a standing serial reaction time task in which they stepped to specific targets. Presented stimuli included random sequences and a blinded repeating sequence. Participants were randomly assigned to one of three groups: LD ( n = 15, 6 practice trials equaling 144 steps), PtP ( n = 14, practice until reaching an estimated personal plateau in performance), or OVP ( n = 12, practice 100% more trials after reaching an estimated plateau in performance). Measures of task-specific learning (i.e., faster speed on retention tests) and transfer of learning were performed after 2–4 days of no practice. Learning of the random sequence was greater for the OVP group compared to the LD group ( p = 0.020). The OVP ( p = 0.004) and PtP ( p = 0.010) groups learned the repeated sequence more than the LD group, although the number of practice trials across groups more strongly predicted learning ( p = 0.020) than did group assignment (OVP vs. PtP, p = 0.270). No group effect was observed for transfer, although significant transfer was observed in this study as a whole ( p < 0.001). Overall, high and personalized dosages of postural training were well-tolerated by older adults, suggesting that this approach is clinically feasible. Practicing well-beyond standard dosages also improved motor learning. Further research should determine the clinical benefit of this personalized approach, and if one of the personalized approaches (PtP vs. OVP) is more beneficial than the other for older patients.
... The reason for the above is that already the number of task repetition required for recovery has been reported [17,18,[40][41][42]. This number ranges between 300 and 1000 per day and is as high as possible to help induce recovery of motor function [43]. ...
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Background: High repetitions of task practice is required for the recovery of the motor function during constraint-induced movement therapy (CIMT). This can be achieved into ways: when the task practice is measured in hours of practice or when the number of repetitions is counted. However, it has been argued that using hours of task practice as a measure of practice does not provide a clear instruction on the dose of practice. Aim: The aim of this study is to determine the feasibility and effects of the CIMT protocol that uses the number of repetitions of task practice. Materials/method: The study was a systematic review registered in PROSPERO (CRD42020142140). Five databases, PubMED, CENTRAL, PEDro, OTSeeker and Web of Science, were searched. Studies of any designs in adults with stroke were included if they used the number of repetitions of task practice as a measure of dose. The methodological quality of the included studies was assessed using Modified McMaster critical review form. The results were analysed using qualitative synthesis. Results: Eight studies (n = 205) were included in the study. The number of task repetitions in the studies ranges between 45 and 1280 per day. The results showed that CIMT protocol using the number of repetitions of task practice was feasible and improved outcomes such as motor function, quality of life, functional mobility and spasticity. Conclusion: The number of repetitions of task practice as a measure of CIMT dose can be used in place of the existing protocol that uses the number of hours of task practice.
... Repetitions per session will be split across three tasks to allow for variability in task practice and to avoid the boredom that might come from repeatedly practicing a single task. As previous animal and human studies [27][28][29], which were designed to investigate motor learning and motor function, employed large amounts of practice ranging between 300 and 800 repetitions per session, we chose 300 repetitions (100 per task-based activity). Encouraging verbal cues will be provided by the therapist to the participant for maintaining the interest and motivation. ...
Article
Introduction: Game-based rehabilitation is an emerging therapeutic intervention that allows intensive, repetitive, task-based training to improve upper limb (UL) function following stroke, based on the principles of neuro-plasticity and motor (re)learning. Rehabilitation using commercial gaming system will be motivating, enjoyable, challenging and affordable. Therefore, the present study aims at assessing the effectiveness of an intensive, functional, gamified rehabilitation program using the ArmAble™ device in improving UL motor function in people with stroke. Method: In this single-blinded, multi-centric, randomized clinical trial, 120 adults with acute/sub-acute unilateral stroke will be randomized to receive an intensive, functional, gamified training program using the ArmAble™ or task-based training along with a conventional therapy for 2 h/day, 6 days/week for 2 weeks, followed by a home-based, functional rehabilitation program for another 4 weeks (~30 min/day, 6 days/week). Primary outcomes evaluated by a blinded assessor at the baseline, 2 weeks and 6 weeks' post-intervention will include Fugl-Meyer assessment - upper extremity and Action research arm test. A linear mixed effect regression model or relevant non-parametric tests will be used to analyze the data for all outcomes. An intention-to-treat analysis will be used with missing data handled by multiple imputation. Discussion: Rehabilitation provided with the ArmAble™ device, if found effective, can be used from the early stages post-stroke to provide intensive, repetitive, gamified training to improve UL motor function. Trial registration number: CTRI/2020/09/027651.
... There is also the issue of the accuracy of the skill being performed, as this influences the cortical representations more than simply increased use alone [4,25,26]. In the design of this study, this was addressed by turning off the 'autocorrect' feature on the cell phones. ...
Article
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Cortical representations expand during skilled motor learning. We studied a unique model of motor learning with cellular phone texting, where the thumbs are used exclusively to interact with the device and the prominence of use can be seen where 3200 text messages are exchanged a month in the 18–24 age demographic. The purpose of the present study was to examine the motor cortex representation and input–output (IO) recruitment curves of the abductor pollicis brevis (APB) muscle of the thumb and the ADM muscle with transcranial magnetic stimulation (TMS), relative to individuals’ texting abilities and short-term texting practice. Eighteen individuals performed a functional texting task (FTT) where we scored their texting speed and accuracy. TMS was then used to examine the cortical volumes and areas of activity in the two muscles and IO curves were constructed to measure excitability. Subjects also performed a 10-min practice texting task, after which we repeated the cortical measures. There were no associations between the cortical measures and the FTT scores before practice. However, after practice the APB cortical map expanded and excitability increased, whereas the ADM map constricted. The increase in the active cortical areas in APB correlated with the improvement in the FTT score. Based on the homogenous group of subjects that were already good at texting, we conclude that the cortical representations and excitability for the thumb muscle were already enlarged and more receptive to changes with short-term practice, as noted by the increase in FTT performance after 10-min of practice.
... A substantial body of work has shown that targeted strokes in the motor-sensory areas lead to the displacement or formation of new motor maps in adjoining cortical zones. [94][95][96][97] Map displacement is dependent on the location of the infarct. Map displacement is more prevalent following strokes to the somatosensory cortex where remapping of sensory forelimb function is seen in the motor cortex, although this does not reciprocate in the event of a stroke to the motor cortex. ...
Article
Stroke is a debilitating disease. Current effective therapies for stroke recovery are limited to neurorehabilitation. Most stroke recovery occurs in a limited and early time window. Many of the mechanisms of spontaneous recovery after stroke parallel mechanisms of normal learning and memory. While various efforts are in place to identify potential drug targets, an emerging approach is to understand biological correlates between learning and stroke recovery. This review assesses parallels between biological changes at the molecular, structural, and functional levels during learning and recovery after stroke, with a focus on drug and cellular targets for therapeutics.
... The pia mater was attached to skull using a 2-octyl and n-butyl cyanoacrylate tissue adhesive (Leukosan, BSN Medical GmbH, Germany) in order to prevent dimpling during lowering the microelectrode arrays (Kralik et al., 2001). The arrays were centered stereotaxically to target forelimb area (AP: +1.5 mm, ML: ±2.5 mm) in both hemispheres (Gioanni and Lamarche, 1985;Kleim et al., 1998) and advanced independently and slowly (50 µm/min) to a cortical depth of ~1200 µm using a hydraulic micropositioner (Narishige MO-82, Japan). When the target depth is achieved, the craniotomy was sealed with a thin layer of cyanoacrylate tissue adhesive and the microelectrode array was fixed to the skull using dental acrylic. ...
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Objective: Brain-machine interfaces (BMIs) are promising candidates for restoring the lost motor system functions. Center-out reaching task is a commonly used BMI control paradigm in humans and monkeys. In this work, our goal was to develop a behavioral paradigm which enables rats to control a neuroprosthesis in a center-out reaching task applied in one-dimensional space. Approach: The experimental setup mainly consisted of a behavioral cage and a robotic workspace outside the cage. Two distant targets were located on the left and right sides of the central starting position of the robot endpoint. An online transform algorithm was used to convert the activity of a pair of recorded primary motor cortex units into two robotic actions. An increase in the activity of one of the units directed the robot endpoint toward left while an increase in the other moved it toward right. The task difficulty level which was proportional to the distance between the selected target and the initial position of the robot endpoint at the beginning of trials was increased gradually as the rat adapts with the transform. Main Results: All three rats involved in the study were capable of achieving randomly selected targets with at least 78% accuracy in the highest task difficulty level, in center-out reaching task. A total of 9 out of 16 pairs of units examined were eligible for training in center-out reaching task. Two out of three rats were capable of reversal learning where the mapping between the activity of the unit pairs and the robotic actions were reversed. Significance: The present behavioral paradigm and experimental setup may be used to study the neural mechanisms involved in neuroprosthetic control. Using the present approach the performance of BMI decoders may also be assessed for one-dimensional center-out reaching task.
... Such maps are obtained through systematic grid-like stimulation of the motor cortical area and measurement of the elicited muscle activity in the body. Training prehension tasks in rodents has been associated with an expansion of the territory for the trained effectors (Kleim et al., 1998). One study on humans learning a motor sequence showed an increase in the size of motor maps and cortico-motor-neuronal excitability of the digits measured by TMS (Pascual-Leone et al., 1994). ...
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This is the second chapter of the series on the use of clinical neurophysiology for the study of movement disorders. It focusses on methods that can be used to probe neural circuits in brain and spinal cord. These include use of spinal and supraspinal reflexes to probe the integrity of transmission in specific pathways; transcranial methods of brain stimulation such as transcranial magnetic stimulation and transcranial direct current stimulation, which activate or modulate (respectively) the activity of populations of central neurones; EEG methods, both in conjunction with brain stimulation or with behavioural measures that record the activity of populations of central neurones; and pure behavioural measures that allow us to build conceptual models of motor control. The methods are discussed mainly in relation to work on healthy individuals. Later chapters will focus specifically on changes caused by pathology.
... The motor maps can be assumed to be fundamentally the same in children and adults, but little is known regarding how local network properties within M1 evolve during maturation and how these are associated with concomitant changes in the motor repertoire. There are some key findings emerging from animal models on the use-dependent map plasticity related to the learning of motor skills Kleim et al. 1998). It has been suggested that the emergence of fine motor control is associated with a relative broadening of connectivity between functionally diverse cortical motor neurons and changes in synaptic properties that could enable the emergence of smaller independent networks (Biane et al. 2015;Arcaro et al. 2019). ...
Article
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The development of the organization of the motor representation areas in children and adolescents is not well-known. This cross-sectional study aimed to provide an understanding for the development of the functional motor areas of the upper extremity muscles by studying healthy right-handed children (6–9 years, n = 10), preadolescents (10–12 years, n = 13), adolescents (15–17 years, n = 12), and adults (22–34 years, n = 12). The optimal representation site and resting motor threshold (rMT) for the abductor pollicis brevis (APB) were assessed in both hemispheres using navigated transcranial magnetic stimulation (nTMS). Motor mapping was performed at 110% of the rMT while recording the EMG of six upper limb muscles in the hand and forearm. The association between the motor map and manual dexterity (box and block test, BBT) was examined. The mapping was well-tolerated and feasible in all but the youngest participant whose rMT exceeded the maximum stimulator output. The centers-of-gravity (CoG) for individual muscles were scattered to the greatest extent in the group of preadolescents and centered and became more focused with age. In preadolescents, the CoGs in the left hemisphere were located more laterally, and they shifted medially with age. The proportion of hand compared to arm representation increased with age (p = 0.001); in the right hemisphere, this was associated with greater fine motor ability. Similarly, there was less overlap between hand and forearm muscles representations in children compared to adults (p
... This corresponded to an average of 8.3 repetitions per minute and an average of 211.8 repetitions per session. This amount of therapy is over four times the number of repetitions typically performed during a clinician-directed outpatient treatment session [20,21] and is closer to repetition intensity thresholds that have increased cortical representations in animal studies [22][23][24]. ...
... In stroke patients, recent studies have shown that targeted high-intensity training can reduce impairments and increase functional activity even in the chronic stage [1], [2]. These results are in line with the animal studies by Nudo et al. in stroke models; monkeys performed 600 repetitions of a pellet retrieval task per day which helped reverse the impairments due to a cortical lesion [3], [4]. However, in stark contrast to these observations, the current rehabilitation dose is reported to be as low as 53 active movements and 32 functional repetitions every session across the entire upper limb [5]. ...
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Hand neurorehabilitation involves the training of movements at various joints of the forearm, wrist, fingers, and thumb. Assisted training of all these joints either requires either one complex multiple degree-of-freedom (DOF) robot or a set of simple robots with one or two DOF. Both of these are not economically or clinically viable solutions. The paper presents work that addresses this problem with a single DOF robot that can train multiple joints one at a time – the plug and train robot (PLUTO). PLUTO has a single actuator with a set of passive attachments/mechanisms that can be easily attached/detached to train for wrist flexion-extension, wrist ulnar-radial deviation, forearm pronation-supination, and gross hand opening-closings. The robot can provide training in active and assisted regimes. PLUTO is linked to performance adaptive computer games to provide feedback to the patients and motivate them during training. As the first step toward clinical validation, the device's usability was evaluated in 45 potential stakeholders/end-users of the device, including 15 patients, 15 caregivers, and 15 clinicians with standardized questionnaires: System Usability Scale (SUS) and User Experience Questionnaire (UEQ). Patients and caregivers were administered the questionnaire after a two-session training. Clinicians, on the other hand, had a single session demo after which feedback was obtained. The total SUS score obtained from the patients, clinicians, and healthy subjects was 73.3 ± 14.6 (n = 45), indicating good usability. The UEQ score was rated positively in all subscales by both the patients and clinicians, indicating that the features of PLUTO match their expectations. The positive response from the preliminary testing and the feedback from the stakeholders indicates that with additional passive mechanisms, assessment features, and optimized ergonomics, PLUTO will be a versatile, affordable, and useful system for routine use in clinics and also patients’ homes for delivering minimally supervised hand therapy.
... Second, we conducted a dose-matched trial for additional therapy time, which, for both groups, was two times 30 min per day. However, number of repetitions could be different between both groups with a higher number of repetitions for the motor group, which is known to be a beneficial factor for recovery (36,37). This difference in number of repetitions could be explained by the nature of the exercises. ...
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Background: Somatosensory function plays an important role in motor learning. More than half of the stroke patients have somatosensory impairments in the upper limb, which could hamper recovery. Question: Is sensorimotor upper limb (UL) therapy of more benefit for motor and somatosensory outcome than motor therapy? Design: Randomized assessor- blinded multicenter controlled trial with block randomization stratified for neglect, severity of motor impairment, and type of stroke. Participants: 40 first-ever stroke patients with UL sensorimotor impairments admitted to the rehabilitation center. Intervention: Both groups received 16 h of additional therapy over 4 weeks consisting of sensorimotor ( N = 22) or motor ( N = 18) UL therapy. Outcome measures: Action Research Arm test (ARAT) as primary outcome, and other motor and somatosensory measures were assessed at baseline, post-intervention and after 4 weeks follow-up. Results: No significant between-group differences were found for change scores in ARAT or any somatosensory measure between the three time points. For UL impairment (Fugl-Meyer assessment), a significant greater improvement was found for the motor group compared to the sensorimotor group from baseline to post-intervention [mean (SD) improvement 14.65 (2.19) vs. 5.99 (2.06); p = 0.01] and from baseline to follow-up [17.38 (2.37) vs. 6.75 (2.29); p = 0.003]. Conclusion: UL motor therapy may improve motor impairment more than UL sensorimotor therapy in patients with sensorimotor impairments in the early rehabilitation phase post stroke. For these patients, integrated sensorimotor therapy may not improve somatosensory function and may be less effective for motor recovery. Clinical Trial Registration: www.ClinicalTrials.gov , identifier NCT03236376.
... 18,40,41 The amount of challenge, titrated by the amount of problem-solving required for task success, has also been shown to promote engagement as well as enhance subsequent motor recovery and motor learning. [42][43][44][45][46][47] A study does not need to include all these elements of experience-dependent plasticity to make it impactful, but it should be philosophically grounded in these ideas. ...
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Neurorehabilitation relies on core principles of neuroplasticity to activate and engage latent neural connections, promote detour circuits, and reverse impairments. Clinical interventions incorporating these principles have been shown to promote recovery and demote compensation. However, many clinicians struggle to find interventions centered on these principles in our nascent, rapidly growing body of literature. Not to mention the immense pressure from regulatory bodies and organizational balance sheets that further discourage time-intensive recovery-promoting interventions, incentivizing clinicians to prioritize practical constraints over sound clinical decision making. Modern neurorehabilitation practices that result from these pressures favor strategies that encourage compensation over those that promote recovery. To narrow the gap between the busy clinician and the cutting-edge motor recovery literature, we distilled 5 features found in early-phase clinical intervention studies—ones that value the more enduring biological recovery processes over the more immediate compensatory remedies. Filtering emerging literature through this lens and routinely integrating promising research into daily practice can break down practical barriers for effective clinical translation and ultimately promote durable long-term outcomes. This perspective is meant to serve a new generation of mechanistically minded and caring clinicians, students, activists, and research trainees, who are poised to not only advance rehabilitation science, but also erect evidence-based policy changes to accelerate recovery-based stroke care.
... Notably, M1 plays a crucial role in ML, as evidenced in several animal studies [21][22][23][24]. In humans, early studies using transcranial magnetic stimulation (TMS) showed that learning various motor tasks was associated with a functional reorganization of M1, as assessed by corticospinal excitability changes [19,25,26], and modulation of M1 excitability by rTMS modified ML in healthy subjects [27][28][29][30]. ...
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Numerous studies have noted that sex and/or menstrual phase influences cognitive performance (in particular, declarative memory), but the effects on motor learning (ML) and procedural memory/consolidation remain unclear. In order to test the hypothesis that ML differs across menstrual cycle phases, initial ML, overlearning, consolidation, and final performance were assessed in women in the follicular, preovulation and luteal phases. Primary motor cortex (M1) oscillations were assessed neuro-physiologically, and premenstrual syndrome and interoceptive awareness scores were assessed psychologically. We found not only poorer performance gain through initial ML but also lower final performance after overlearning a day and a week later in the luteal group than in the ovulation group. This behavioral difference could be explained by particular premenstrual syndrome symptoms and associated failure of normal M1 excitability in the luteal group. In contrast, the offline effects, i.e., early and late consolidation, did not differ across menstrual cycle phases. These results provide information regarding the best time in which to start learning new sensorimotor skills to achieve expected gains.
... In addition to exhibiting a reduced repertoire of locomotor gaits over a wide range of treadmill speeds [72,92], adult Dscam 2J mutant mice show voluntary motor control impairments while walking on the rungs of a horizontal ladder or while stepping over an obstacle during treadmill locomotion [51], thus arguing for neurological changes within the motor cortex and its corticospinal tract. The motor cortex exhibits cortical representations of the whole body, with territories specifically dedicated to the control of the arm or the leg, for example [184][185][186][187][188][189][190]. Within a cortical representation, the motor cortex is organized in 6 layers, with upper layers containing cortical neurons integrating and processing thalamic and cortical inputs from other brain regions and deeper layers in which cortical neurons project to other regions, such as corticospinal neurons projecting in the spinal cord [191][192][193][194][195]. ...
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Locomotion results in an alternance of flexor and extensor muscles between left and right limbs generated by motoneurons that are controlled by the spinal interneuronal circuit. This spinal locomotor circuit is modulated by sensory afferents, which relay proprioceptive and cutaneous inputs that inform the spatial position of limbs in space and potential contacts with our environment respectively, but also by supraspinal descending commands of the brain that allow us to navigate in complex environments, avoid obstacles, chase prey, or flee predators. Although signaling pathways are important in the establishment and maintenance of motor circuits, the role of DSCAM, a cell adherence molecule associated with Down syndrome, has only recently been investigated in the context of motor control and locomotion in the rodent. DSCAM is known to be involved in lamination and delamination, synaptic targeting, axonal guidance, dendritic and cell tiling, axonal fasciculation and branching, programmed cell death, and synaptogenesis, all of which can impact the establishment of motor circuits during development, but also their maintenance through adulthood. We discuss herein how DSCAM is important for proper motor coordination, especially for breathing and locomotion.
... This could be seen even when executing acrobatic tasks that required considerable coordination between anterior and posterior limbs, and also with the rest of the body, corroborating with data found in the literature [38]. In addition, our data also showed a rapid acquisition phase, followed by a motor sequence consolidation phase, with a gradual change in motor performance in the late learning phase, which corroborates findings from several studies that used different training protocols [38,55,56]. Reduced time to finish complex motor tasks was also verified by previous studies [26,28[38], suggesting that behavior changes, such as diminished hesitation and less pelvic member stimulation, can be associated with motor learning of complex skills [57]. ...
Article
Learning complex motor skills is an essential process in our daily lives. Moreover, it is an important aspect for the development of therapeutic strategies that refer to rehabilitation processes since motor skills previously acquired can be transferred to similar tasks (motor skill transfer) or recovered without further practice after longer delays (motor skill retention). Different acrobatic exercise training (AE) protocols induce plastic changes in areas involved in motor control and improvement in motor performance. However, the plastic mechanisms involved in the retention of a complex motor skill, essential for motor learning, are not well described. Thus, our objective was to analyze the brain plasticity mechanisms involved in motor skill retention in AE . Motor behavior tests, and the expression of synaptophysin (SYP), synapsin-I (SYS), and early growth response protein 1 (Egr-1) in brain areas involved in motor learning were evaluated. Young male Wistar rats were randomly divided into 3 groups: sedentary (SED), AE, and AE with retention period (AER). AE was performed three times a week for 8 weeks, with 5 rounds in the circuit. After a fifteen-day retention interval, the AER animals was again exposed to the acrobatic circuit. Our results revealed motor performance improvement in the AE and AER groups. In the elevated beam test, the AER group presented a lower time and greater distance, suggesting retention period is important for optimizing motor learning consolidation. Moreover, AE promoted significant plastic changes in the expression of proteins in important areas involved in control and motor learning, some of which were maintained in the AER group. In summary, these data contribute to the understanding of neural mechanisms involved in motor learning in an animal model, and can be useful to the construction of therapeutics strategies that optimize motor learning in a rehabilitative context.
... CSN BC-lat cervical collaterals extend more ventrally than cervical collaterals from CSN medial , which is reminiscent of CSN collaterals from the rostral versus caudal forelimb cortex in cats (Martin, 1996). CSN BC-lat projections might play distinct function(s) compared to CSN medial projections; for example, digit movement in rats is almost entirely evoked by stimulating RFA and not CFA (Kleim et al., 1998). Future investigations of now molecularly distinct CSN subpopulations can elucidate their contributions to distinct aspects of motor control and nonmotor functions. ...
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For precise motor control, distinct subpopulations of corticospinal neurons (CSN) must extend axons to distinct spinal segments, from proximal targets in the brainstem and cervical cord to distal targets in thoracic and lumbar spinal segments. We find that developing CSN subpopulations exhibit striking axon targeting specificity in spinal white matter, which establishes the foundation for durable specificity of adult corticospinal circuitry. Employing developmental retrograde and anterograde labeling, and their distinct neocortical locations, we purified developing CSN subpopulations using fluorescence-activated cell sorting to identify genes differentially expressed between bulbar-cervical and thoracolumbar-projecting CSN subpopulations at critical developmental times. These segmentally distinct CSN subpopulations are molecularly distinct from the earliest stages of axon extension, enabling prospective identification even before eventual axon targeting decisions are evident in the spinal cord. This molecular delineation extends beyond simple spatial separation of these subpopulations in the cortex. Together, these results identify candidate molecular controls over segmentally specific corticospinal axon projection targeting.
... To directly test the hypothesis of whether trial-to-trial variability in M1 neural activity could drive downstream structures to produce kinematic variability, we applied ICMS in M1 under ketamine anesthesia (Fig. 6a, also see Methods). ICMS is known to activate descending fibers from M1 to the motor periphery 37,38 . Thus, ICMS allows us to directly test how movement-related structures downstream from M1 might respond to variability in M1 patterning. ...
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Animals can capitalize on invariance in the environment by learning and automating highly consistent actions; however, they must also remain flexible and adapt to environmental changes. It remains unclear how primary motor cortex (M1) can drive precise movements, yet also support behavioral exploration when faced with consistent errors. Using a reach-to-grasp task in rats, along with simultaneous electrophysiological monitoring in M1 and dorsolateral striatum (DLS), we find that behavioral exploration to overcome consistent task errors is closely associated with tandem increases in M1 and DLS neural variability; subsequently, consistent ensemble patterning returns with convergence to a new successful strategy. We also show that compared to reliably patterned intracranial microstimulation in M1, variable stimulation patterns result in significantly greater movement variability. Our results thus indicate that motor and striatal areas can flexibly transition between two modes, reliable neural pattern generation for automatic and precise movements versus variable neural patterning for behavioral exploration.
... The pia mater was attached to skull using a 2-octyl and n-butyl cyanoacrylate tissue adhesive (Leukosan, BSN Medical GmbH, Germany) in order to prevent dimpling during lowering the microelectrode arrays (Kralik et al., 2001). The arrays were centered stereotaxically to target forelimb area (AP: +1.5 mm, ML: ± 2.5 mm) in both hemispheres (Gioanni and Lamarche, 1985;Kleim et al., 1998) and advanced independently and slowly (50 µm/min) to a cortical depth of ~1200 µm using a hydraulic micropositioner (Narishige MO-82, Japan). When the target depth was achieved, the craniotomy was sealed with a thin layer of cyanoacrylate tissue adhesive and the microelectrode array was fixed to the skull using dental acrylic. ...
Article
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Background Controlling the trajectory of a neuroprosthesis to reach distant targets is a commonly used brain-machine interface (BMI) task in primates and has not been available for rodents yet. New Method Here, we describe a novel, fine-tuned behavioral paradigm and setup which enables this task for rats in one-dimensional space for reaching two distant targets depending on their limited cognitive and visual capabilities compared to those of primates. An online transform was used to convert the activity of a pair of primary motor cortex (M1) units into two robotic actions. The rats were shaped to adapt to the transform and direct the robotic actuator toward the selected target by modulating the activity of the M1 neurons. Results All three rats involved in the study were capable of achieving randomly selected targets with at least 78% accuracy. A total of 9 out of 16 pairs of units examined were eligible for exceeding this success criterion. Two out of three rats were capable of reversal learning, where the mapping between the activity of the M1 units and the robotic actions were reversed. Comparison with Existing Methods The present work is the first demonstration of trajectory-based control of a neuroprosthetic device by rodents to reach two distant targets using visual feedback. Conclusion The behavioral paradigm and setup introduced here can be used as a cost-effective platform for elucidating the information processing principles in the neural circuits related to neuroprosthetic control and for studying the performance of novel BMI technologies using freely moving rats.
... Although is known that training intensity (i.e., rehabilitation dose) impacts neural reorganization and motor outcomes, optimal treatment doses and intensity thresholds have not been clearly established (3,4). Repeated practice of challenging movements is key to enhance motor system connectivity and restore motor function: animal models of stroke have shown that over 400 movements per session are required for this to occur (3,(5)(6)(7)(8)(9)(10). However, such a high level of repetition is not feasible within conventional rehabilitation sessions (11). ...
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Introduction Robot-based training integrated into usual care might optimize therapy productivity and increase treatment dose. This retrospective study compared two doses of an upper limb rehabilitation program combining robot-assisted therapy and occupational therapy on motor recovery and costs after stroke. Methods Thirty-six subacute stroke patients [Fugl-Meyer Assessment (FMA) score 32 ± 12 points; mean ± SD] underwent a combined program of 29 ± 3 sessions of robot-assisted therapy and occupational therapy. Scheduled session time for the higher dose group (HG) was 90 min (two 45-min sessions; n = 14) and for the lower dose group (LG) was 60 min (two 30-min sessions; n = 22). Pre-/post-treatment change in FMA score (ΔFMA, %), actual active time (min), number of movements and number of movements per minute per robot-assisted therapy session were compared between groups. The costs of the combined programs were also analyzed. Results ΔFMA did not differ significantly between groups; the HG improved by 16 ± 13 % and the LG by 11 ± 8%. A between-group difference was found for actual active time ( p = 1.06E ⁻¹³ ) and number of movements ( p = 4.42E ⁻² ) but not for number of movements per minute during robot-assisted therapy: the HG performed 1,023 ± 344 movements over 36 ± 3 min and the LG performed 796 ± 301 movements over 29 ± 1 min. Both groups performed 28 movements per minute. The combined program cost was €2017 and €1162 for HG and LG, respectively. Conclusions Similar motor improvements were observed following two doses of movement-based training. The reduction in scheduled session time did not affect the intensity of the practice and met economic constraints.
... 33,36,37 Expansion of distal forelimb functional representations has been observed in M1 of both rats and monkeys following motor skill training. 22,24,38 Similar neuroanatomical and neurophysiological changes are expected to occur in anatomically and functionally connected pre-motor and sensory areas in both normal and cortically injured animals, and these changes may be enhanced with behavioral interventions such as skilled motor use or CIMT. ...
Article
Background: Physical use of the affected upper extremity can have a beneficial effect on motor recovery in people after stroke. Few studies have examined neurological mechanisms underlying the effects of forced use in non-human primates. In particular, the ventral premotor cortex (PMV) has been previously implicated in recovery after injury. Objective: To examine changes in motor maps in PMV after a period of forced use following ischemic infarct in primary motor cortex (M1). Methods: Intracortical microstimulation (ICMS) techniques were used to derive motor maps in PMV of four adult squirrel monkeys before and after an experimentally induced ischemic infarct in the M1 distal forelimb area (DFL) in the dominant hemisphere. Monkeys wore a sleeved jacket (generally 24 hrs/day) that forced limb use contralateral to the infarct in tasks requiring skilled digit use. No specific rehabilitative training was provided. Results: At 3 mos post-infarct, ICMS maps revealed a significant expansion of the DFL representation in PMV relative to pre-infarct baseline (mean = +77.3%; n = 3). Regression analysis revealed that the magnitude of PMV changes was largely driven by M1 lesion size, with a modest effect of forced use. One additional monkey examined after ∼18 months of forced use demonstrated a 201.7% increase, unprecedented in non-human primate studies. Conclusions: Functional reorganization in PMV following an ischemic infarct in the M1 DFL is primarily driven by M1 lesion size. Additional expansion occurs in PMV with extremely long periods of forced use but such extended constraint is not considered clinically feasible.
... Acrobatic training is described as complex visuomotor learning and motor activities that leads to acquisition of new motor skills improving the animal's coordination and problem-solving performance [24]. The main effects of acrobatic training have been reported on the cerebellum and cortex of healthy rats [24][25][26][27][28][29] ranging from increase in the number of synapses [24,26], plasticity of dendritic spines [27], increase in BDNF expression [30] and increase in the synaptic proteins levels: synaptophysin, synapsin I, microtubule-associated protein 2 and neurofilaments [31,32]. Another set of evidence indicates that acrobatic training causes experience-dependent glial changes, that is, an increase of astrocyte volume in the molecular layer of Purkinje cells in cerebellar córtex [25,33]. ...
Article
Chronic cerebral hypoperfusion leads to neuronal loss in the hippocampus and spatial memory impairments. Physical exercise is known to prevent cognitive deficits in animal models; and there is evidence of sex differences in behavioral neuroprotective approaches. The aim of present study was to investigate the effects of acrobatic training in male and female rats submitted to chronic cerebral hypoperfusion. Males and females rats underwent 2VO (two-vessel occlusion) surgery and were randomly allocated into 4 groups of males and 4 groups of females, as follows: 2VO acrobatic, 2VO sedentary, Sham acrobatic and Sham sedentary. The acrobatic training started 45 days after surgery and lasted 4 weeks; animals were then submitted to object recognition and water maze testing. Brain samples were collected for histological and morphological assessment and flow cytometry. 2VO causes cognitive impairments and acrobatic training prevented spatial memory deficits assessed in the water maze, mainly for females. Morphological analysis showed that 2VO animals had less NeuN labeling and acrobatic training prevented it. Increased number of GFAP positive cells was observerd in females; moreover, males had more branched astrocytes and acrobatic training prevented the branching after 2VO. Flow cytometry showed higher mitochondrial potential in trained animals and more reactive oxygen species production in males. Acrobatic training promoted neuronal survival and improved mitochondrial function in both sexes, and influenced the glial scar in a sex-dependent manner, associated to greater cognitive benefit to females after chronic cerebral hypoperfusion.
... Specifically, animal studies suggested that motor map territory can be a valuable neurophysiological measure for quantifying the neural substrate topography and plasticity associated with functional change due to brain injury or motor skill training Nudo, Wise, et al., 1996). Important findings pertinent to rehabilitation include observations that skill training-induced improvements in motor function can be accompanied by expansion of map area and normalization of corticospinal neuron distribution in the spinal cord (Friel et al., 2000(Friel et al., , 2012Kleim et al., 1998). ...
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Brain stimulation combined with intensive therapy may improve hand function in children with perinatal stroke-induced unilateral cerebral palsy (UCP). However, response to therapy varies and underlying neuroplasticity mechanisms remain unclear. Here, we aimed to characterize robotic motor mapping outcomes in children with UCP. Twenty-nine children with perinatal stroke and UCP (median age 11 ± 2 years) were compared to 24 typically developing controls (TDC). Robotic, neuronavigated transcranial magnetic stimulation was employed to define bilateral motor maps including area, volume, and peak motor evoked potential (MEP). Map outcomes were compared to the primary clinical outcome of the Jebsen-Taylor Test of Hand Function (JTT). Maps were reliably obtained in the contralesional motor cortex (24/29) but challenging in the lesioned hemisphere (5/29). Within the contralesional M1 of participants with UCP, area and peak MEP amplitude of the unaffected map were larger than the affected map. When comparing bilateral maps within the contralesional M1 in children with UCP to that of TDC, only peak MEP amplitudes were different, being smaller for the affected hand as compared to TDC. We observed correlations between the unaffected map when stimulating the contralesional M1 and function of the unaffected hand. Robotic motor mapping can characterize motor cortex neurophysiology in children with perinatal stroke. Map area and peak MEP amplitude may represent discrete biomarkers of developmental plasticity in the contralesional M1. Correlations between map metrics and hand function suggest clinical relevance and utility in studies of interventional plasticity.
... To achieve neural plasticity changes in the damaged brain, a large amount of functional movement or practice is needed. In a preclinical study, the animal models typically perform 400 to 600 repetitions of motor tasks per session to allow cortical reorganization (Kleim, Barbay, and Nudo, 1998). However, rehabilitation intervention for patients with stroke is commonly underdosed due to practical constraints. ...
Article
Background: Virtual reality (VR) is an emerging technology and has shown promising outcomes in stroke rehabilitation. VR can create an enriched environment, facilitate task-specific training, and provide multimodal sensorimotor feedback to augment functional recovery by driving the experience-dependent plasticity, which is prominent in the early-stage after stroke. Purpose: This review aimed to systematically identify and examine the feasibility and effectiveness of VR intervention applied within one-month after stroke on functional outcomes of patients. Methods: Randomized controlled trials were searched across six databases published between 2000 and 2021. Two independent reviewers conducted study selection, data extraction, and quality assessment. Physiotherapy Evidence Database (PEDro) scale was used to evaluate the quality of included studies. Qualitative synthesis and meta-analysis were conducted to compare VR-based rehabilitation and conventional rehabilitation. Results: Seventeen randomized controlled trials were included in this review, and all of them meet the criteria for good quality. The results confirmed the feasibility of applying VR in early stroke rehabilitation. In the meta-analyses, there were no significant differences between VR and control on upper extremity function (SMD = 0.22, P = .10), Activities of Daily Living outcomes (SMD = 0.15, P = .11), balance (SMD = 0.18, P = .86), and cognition (SMD = 0.34, P = .06). Conclusion: VR is a feasible approach and demonstrates comparable effectiveness in functional outcomes with conventional rehabilitation in patients with stroke at the early-stage. Further research focusing on the application of VR in acute stroke survivors with adequate sample size, additional follow-up evaluation and valid outcome measures are warranted.
... Previous studies found that 1000 steps/training session by robotic device training for 4 weeks over a range of levels of weight bearing on the hindlimbs led to motor recovery in animals with ischemic lesions, [29][30][31] and 291.5 repetitions per session improved the balance and the gait pattern of stroke patients [32]. The repetition of robot-assisted gait training up to 2000 times per session was sufficient to modulate plasticity in the brain and led to the recovery of motor functions, such as postural and locomotion control [28,32]. ...
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Chronic stroke leads to the impairment of lower limb function and gait performance. After in-hospital rehabilitation, most individuals lack continuous gait training because of the limited number of physical therapists. This study aimed to evaluate the effects of a newly invented gait training machine (I-Walk) on lower limb function and gait performance in chronic stroke individuals. Thirty community-dwelling chronic stroke individuals were allocated to the I-Walk machine group (n = 15) or the overground gait training (control) group (n = 15). Both groups received 30 min of upper limb and hand movement and sit-to-stand training. After that, the I-Walk group received 30 min of I-Walk training, while the control followed a 30-minute overground training program. All the individuals were trained 3 days/week for 8 weeks. The primary outcome of the motor recovery of lower limb impairment was measured using the Fugl–Meyer Assessment (FMA). The secondary outcomes for gait performance were the 6-minute walk test (6 MWT), the 10-meter walk test (10 MWT), and the Timed Up and Go (TUG). The two-way mixed-model ANOVA with the Bonferroni test was used to compare means within and between groups. The post-intervention motor and sensory subscales of the FMA significantly increased compared to the baseline in both groups. Moreover, the 6 MWT and 10 MWT values also improved in both groups. In addition, the mean difference of TUG in the I-Walk was higher than the control. The efficiency of I-Walk training was comparable to overground training and might be applied for chronic stroke gait training in the community.
... Animal studies have provided neurophysiological evidence on short and long-term anatomical and functional changes occurring when animals are exposed to e.g. motor skill learning 27,28 . In humans, motor practice has been shown to induce a facilitation in corticospinal excitability [29][30][31] , expansion of trained muscle representation at the cortical level [32][33][34] , and improved motor performance 13, 30,31,[35][36][37][38] . ...
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Chronic musculoskeletal pain is a major societal problem due to the impact on quality of life and the large financial burden. Arguably, a main reason why chronic musculoskeletal pain management is still suboptimal is that the underlying mechanisms remain undecided. Over the last three decades our understanding of the influence of sensorimotor changes in response to acute and chronic muscle pain has improved. Nonetheless, technological limitations, controversial findings, and knowledge gaps contribute to no overwhelmingly successful rehabilitation regimes for individuals living with chronic musculoskeletal pain. In this respect, the aim of this PhD project was to apply and test novel approaches for modulating the well-known phenomenon of a reduced motor cortical response following a painful episode. This PhD project utilized a well-established pain model for inducing localized transient pain and aimed to modulate the ensuing reduced motor cortical response by engaging the prefrontal and premotor areas of the brain. Premotor cortex activation has been shown able to facilitate primary motor cortex (M1) excitability. Therefore, the objectives of the PhD project were to (1) establish a robust model for inducing a reduction in corticomotor excitability and (2) modulate pain-induced reduction in corticomotor excitability by engaging premotor cortex activity. The first study demonstrated and characterized a robust hypertonic saline paininduced reduction in corticomotor excitability in the small hand, but not forearm musculature, indicating that despite shared corticomotor representation, differential responses can be elicited. The second study showed that performance of a two-back task was ineffective, possibly due to influences related to prefrontal, subcortical, and/or intracortical mechanisms, in modulating the pain-induced reduction in corticomotor excitability, but enhanced pain perception. Finally, the third study provided the first evidence that action observation combined with motor imagery successfully modulated pain-induced reduction in corticomotor excitability, possibly through premotor cortex activation facilitating M1 excitability. In conclusion, the current PhD thesis provides novel evidence on how to modulate pain-induced reduction in corticomotor excitability in the acute phase of muscle pain by action observation and motor imagery. This contributes to our understanding of the malleability of the motor system, and that an easily delivered task such as action observation combined with motor imagery is warranted in future research in managing musculoskeletal pain
Article
Objective The aim of this study was to investigate the effects of EMG-driven robotic rehabilitation on hand motor functions and daily living activities of patients with acute ischemic stroke. Materials & Method A preliminary randomized-controlled, single-blind trial rectuited twenty-four patients with acute ischemic stroke (<1 month after cerebrovascular accident) and randomly allocated to experimental group (EG) and control group (CG). Neurophysiological rehabilitation program was performed to both EG and CG for 5 days a week and totally 15 sessions. The EG also received robotic rehabilitation with the EMG-driven exoskeleton hand robot (Hand of Hope®, Rehab-Robotics Company) 15 sessions over 3 weeks. Hand motor functions (Fugl-Meyer Assessment-Upper Extremity (FMA-UE) and Action Research Arm Test (ARAT)), activities of daily living (Motor Activity Log (MAL)), force and EMG activities of extensor and flexor muscles for the cup test were evaluated before treatment (pretreatment) and after the 15th session (posttreatment). Results Eleven patients (59.91 ± 14.20 yr) in the EG and 9 patients (70 ± 14.06 yr) in the CG completed the study. EG did not provide a significant advantage compared with the CG in FMA-UE, ARAT and MAL scores and cup-force and EMG activities (p > .05 for all). Conclusion In this preliminary study, improvement in motor functions, daily living activities and force were found in both groups. However, addition of the EMG-driven robotic treatment to the neurophysiological rehabilitation program did not provide an additional benefit to the clinical outcomes in 3 weeks in acute stroke patients.
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Understanding the cortical representations of movements and their stability can shed light on improved brain-machine interface (BMI) approaches to decode these representations without frequent recalibration. Here, we characterize the spatial organization (somatotopy) and stability of the bilateral sensorimotor map of forearm muscles in an incomplete-high spinal-cord injury study participant implanted bilaterally in the primary motor and sensory cortices with Utah microelectrode arrays (MEAs). We built representation maps by recording bilateral multiunit activity (MUA) and surface electromyography (EMG) as the participant executed voluntary contractions of the extensor carpi radialis (ECR), and attempted motions in the flexor carpi radialis (FCR), which was paralytic. To assess stability, we repeatedly mapped and compared left- and right-wrist-extensor-related activity throughout several sessions, comparing somatotopy of active electrodes, as well as neural signals both at the within-electrode (multiunit) and cross-electrode (network) levels. Wrist motions showed significant activation in motor and sensory cortical electrodes. Within electrodes, firing strength stability diminished as the time increased between consecutive measurements (hours within a session, or days across sessions), with higher stability observed in sensory cortex than in motor, and in the contralateral hemisphere than in the ipsilateral. However, we observed no differences at network level, and no evidence of decoding instabilities for wrist EMG, either across timespans of hours or days, or across recording area. While map stability differs between brain area and hemisphere at multiunit/electrode level, these differences are nullified at ensemble level.
Article
Growing evidence suggests that Rho GTPases and molecules involved in their signaling pathways play a major role in the development of the central nervous system (CNS). Whole exome sequencing (WES) and de novo examination of mutations, including SNP (Single Nucleotide Polymorphism) in genes coding for the molecules of their signaling cascade, has allowed the recent discovery of dominant autosomic mutations and duplication or deletion of candidates in the field of neurodevelopmental diseases (NDD). Epidemiological studies show that the co-occurrence of several of these neurological pathologies may indeed be the rule. The regulators of Rho GTPases have often been considered for cognitive diseases such as intellectual disability (ID) and autism. But, in a remarkable way, mild to severe motor symptoms are now reported in autism and other cognitive NDD. Although a more abundant litterature reports the involvement of Rho GTPases and signaling partners in cognitive development, molecular investigations on their roles in central nervous system (CNS) development or degenerative CNS pathologies also reveal their role in embryonic and perinatal motor wiring through axon guidance and later in synaptic plasticity. Thus, Rho family small GTPases have been revealed to play a key role in brain functions including learning and memory but their precise role in motor development and associated symptoms in NDD has been poorly scoped so far, despite increasing clinical data highlighting the links between cognition and motor development. Indeed, early impairements in fine or gross motor performance is often an associated feature of NDDs, which then impact social communication, cognition, emotion, and behavior. We review here recent insights derived from clinical developmental neurobiology in the field of Rho GTPases and NDD (autism spectrum related disorder (ASD), ID, schizophrenia, hypotonia, spastic paraplegia, bipolar disorder and dyslexia), with a specific focus on genetic alterations affecting Rho GTPases that are involved in motor circuit development.
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The motor cortex is crucial for the voluntary control of skilled movement in mammals and is topographically organized into representations of the body (motor maps). Intracortical microstimulation of the motor cortex with long-duration pulse trains (LD-ICMS; ~500 ms) evokes complex movements, occurring in multiple joints or axial muscles, with characteristic movement postures and cortical topography across a variety of mammalian species. Although the laboratory mouse is extensively used in basic and pre-clinical research, high-resolution motor maps elicited with electrical LD-ICMS in both sexes of the adult mouse has yet to be reported. To address this knowledge gap, we performed LD-ICMS of the forelimb motor cortex in both male (n = 10) and naturally cycling female (n = 8) C57/BL6J mice under light ketamine-xylazine anesthesia. Complex and simple movements were evoked from historically defined caudal (CFA) and rostral (RFA) forelimb areas. Four complex forelimb movements were identified consisting of Elevate, Advance, Dig, and Retract postures with characteristic movement sequences and endpoints. Furthermore, evoked complex forelimb movements and cortical topography in mice were organized within the CFA in a unique manner relative to a qualitative comparison with the rat.
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Bone marrow mononuclear cells (BMMCs) have been identified as a relevant therapeutic strategy for the treatment of several chronic diseases of the central nervous system. The aim of this work was to evaluate whether intravenous treatment with BMMCs facilitates the reconnection of lesioned cortico-cortical and cortico-striatal pathways, together with motor recovery, in injured adult Wistar rats using an experimental model of unilateral focal neocortical ischaemia. Animals with cerebral cortex ischaemia underwent neural tract tracing for axonal fibre analysis, differential expression analysis of genes involved in apoptosis and neuroplasticity by RT-qPCR, and motor performance assessment by the cylinder test. Quantitative and qualitative analyses of axonal fibres labelled by an anterograde neural tract tracer were performed. Ischaemic animals treated with BMMCs showed a significant increase in axonal sprouting in the ipsilateral neocortex and in the striatum contralateral to the injured cortical areas compared to untreated rodents. In BMMC-treated animals, there was a trend towards upregulation of the Neurotrophin-3 gene compared to the other genes, as well as modulation of apoptosis by BMMCs. On the 56th day after ischaemia, BMMC-treated animals showed significant improvement in motor performance compared to untreated rats. These results suggest that in the acute phase of ischaemia, Neurotrophin-3 is upregulated in response to the lesion itself. In the long run, therapy with BMMCs causes axonal sprouting, reconnection of damaged neuronal circuitry and a significant increase in motor performance.
Chapter
During the past century, we have seen the development of several therapeutic approaches for the treatment of adults with various neurological deficits. In the early to the middle part of the twentieth century, therapeutic approach for handling neurological conditions was largely orthopedic that emphasized on surgery, strengthening the weak muscles, and use of splints. By the late 1940s to early 1960s, a swing towards a neurological emphasis characterized by development of techniques based on neurophysiological and motor learning principles was observed. Approaches developed by Rood, Brunnström, Bobath and Bobath, and Knot and Voss were instances for the same. From the 1980s the emphasis moved away from the neurodevelopmental approaches towards non-neurodevelopmental approaches like motor relearning program and constraint-induced movement therapy and currently, the technological advancement has paved the way to novel concepts like the use of virtual reality, transcranial magnetic stimulation, and robotics in the field of neurological rehabilitation. As yet, there is no scientific evidence that clearly supports that any standalone approach is superior to another. The gamut of research including systematic and meta-analysis studies has shown minimal to moderate improvement for few approaches when delivered as a standalone treatment and for most the sample size or methodology was not rigorous enough to demand a change in practice. Therapists must have adequate knowledge, both theoretical and practical, about various therapeutic approaches to provide an eclectic treatment program. Since all these approaches have strengths and weaknesses of their own and collectively have the edge over a standalone, an eclectic approach makes it all the more meaningful to tackle most of the sensorimotor dysfunctions among patients. The author believes that the knowledge earned from each scientific therapeutic approach must serve as a reservoir from which a clinician can wisely choose the necessary tools to customize the eclectic treatment program to suit the specific needs of patients. Choosing the best treatment methods to address the patient’s sensorimotor issues must be the most rational approach when substantial evidence for the effectiveness of any single approach over the others is unavailable. Based on the patient’s abilities and requirements, the therapists need to carefully select the strategies that have the greatest chance of successfully remediating existing impairments and promoting functional recovery.
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The learning of motor skills relies on plasticity of the primary motor cortex as task acquisition drives the remodeling of cortical motor networks. Large scale cortical remodeling of evoked motor outputs occurs in response to the learning of skilled, corticospinal-dependent behavior, but not simple, unskilled tasks. Here we determine the response of corticospinal neurons to both skilled and unskilled motor training and assess the role of corticospinal neuron activity in the execution of the trained behaviors. Using in vivo calcium imaging, we found that refinement of corticospinal activity correlated with the development of skilled, but not unskilled, motor expertise. Animals that failed to learn our skilled task exhibited a limited repertoire of dynamic movements and a corresponding absence of network modulation. Transection of the corticospinal tract and aberrant activation of corticospinal neurons show the necessity for corticospinal network activity patterns in the execution of skilled, but not unskilled, movement. We reveal a critical role for corticospinal network modulation in the learning and execution of skilled motor movements. The integrity of the corticospinal tract is essential to the recovery of voluntary movement after central nervous system injuries and these findings should help to shape translational approaches to motor recovery.
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Animals acquire motor skills to better survive and adapt to a changing environment. The ability to learn novel motor actions without disturbing learned ones is essential to maintaining a broad motor repertoire. During motor learning, the brain makes a series of adjustments to build novel sensory–motor relationships that are stored within specific circuits for long-term retention. The neural mechanism of learning novel motor actions and transforming them into long-term memory still remains unclear. Here we review the latest findings with regard to the contributions of various brain subregions, cell types, and neurotransmitters to motor learning. Aiming to seek therapeutic strategies to restore the motor memory in relative neurodegenerative disorders, we also briefly describe the common experimental tests and manipulations for motor memory in rodents.
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Cortical parvalbumin-expressing (Pvalb¹) neurons provide robust inhibition to neighboring pyramidal neurons, crucial for the proper functioning of cortical networks. This class of inhibitory neurons undergoes extensive synaptic formation and maturation during the first weeks after birth and continue to dynamically maintain their synaptic output throughout adulthood. While several transcription factors, such as Nkx2-1, Lhx6, and Sox6, are known to be necessary for the differentiation of progenitors into Pvalb¹ neurons, which transcriptional programs underlie the postnatal maturation and maintenance of Pvalb¹ neurons’ innervation and synaptic function remains largely unknown. Because Sox6 is continuously expressed in Pvalb¹ neurons until adulthood, we used conditional knock-out strategies to investigate its putative role in the postnatal maturation and synaptic function of cortical Pvalb¹ neurons in mice of both sexes. We found that early postnatal loss of Sox6 in Pvalb¹ neurons leads to failure of synaptic bouton growth, whereas later removal in mature Pvalb¹ neurons in the adult causes shrinkage of already established synaptic boutons. Paired recordings between Pvalb¹ neurons and pyramidal neurons revealed reduced release probability and increased failure rate of Pvalb¹ neurons’ synaptic output. Furthermore, Pvalb¹ neurons lacking Sox6 display reduced expression of full-length tropomyosin-receptor kinase B (TrkB), a key modulator of GABAergic transmission. Once re-expressed in neurons lacking Sox6, TrkB was sufficient to rescue the morphologic synaptic phenotype. Finally, we showed that Sox6 mRNA levels were increased by motor training. Our data thus suggest a constitutive role for Sox6 in the maintenance of synaptic output from Pvalb¹ neurons into adulthood.
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Background: Arthrolysis is usually performed when stiffness has a disabling effect on quality of life and in cases where physiotherapy has not been effective. This report describes one patient with a chronic stiff wrist who underwent open arthrolysis. The purpose of this case report is to describe the rehabilitation following arthrolysis, in order to illustrate the effects of intensive physiotherapy for this patient. Case description: A 54-year-old woman with chronic wrist stiffness secondary to a radio-ulnar fracture was described. The patient presented severe pain and unsatisfactory wrist range of motion and muscle strength almost 2 years after the traumatic event. Intervention: Post-arthrolysis rehabilitation was based on edema control, manual therapy, transcutaneous electrical nerve stimulation (TENS), static splinting and strengthening exercises. In addition, graded motor imagery and proprioceptive rehabilitation were included to address impaired motor control. Outcome measures of passive range of motion (PROM), active range of motion (AROM), grip and pinch strength, numeric rating scale (NRS), disability of the arm, shoulder and hand (DASH) and patient-rated wrist/hand evaluation (PRWHE) were recorded. Conclusions: The outcomes of this case report suggest that arthrolysis combined with immediate and intensive physiotherapy were a suitable option for the treatment of post-traumatic wrist stiffness in this patient. The passive motion measured intraoperatively was maintained, while pain, functional active motion and strength were improved allowing for social reintegration.
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The primary motor cortex, a dynamic center for overall motion control and decision making, undergoes significant alterations upon neural stimulation. Over the last few decades, data from numerous studies using rodent models have improved our understanding of the morphological and functional plasticity of the primary motor cortex. In particular, spatially specific formation of dendritic spines and their maintenance during distinct behaviors is considered crucial for motor learning. However, whether the modifications of specific synapses are associated with motor learning should be studied further. In this review, we summarized the findings of prior studies on the features and dynamics of the primary motor cortex in rodents.
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Patients with multiple sclerosis, despite advances in therapy, often suffer from locomotor impairment that limits their mobility and affect quality of life. Rehabilitation is part of the treatment of MS and has shown its beneficial effects in numerous studies. While traditional rehabilitation techniques remain in the limelight, new technologies are emerging and make it possible to improve the management of disabling symptoms. The aim of this update is to synthesize the new therapy techniques proposed in rehabilitation for patients with multiple sclerosis according to the symptoms as balance, gait, upper limb disorders, fatigue, spasticity and disease progression published over the past 5 years. With regard to balance and walking disorders, neuromotor rehabilitation, physical exercise, rhythmic auditory stimulation, gait robot training and exergaming are effective. Only physical exercise has shown a positive effect on fatigue management. Spasticity is improved by classic rehabilitation techniques however non-invasive brain stimulation are promising. The rehabilitation of upper limb dysfunctions uses various effective techniques such as the repetition of functional tasks in real or virtual situations. In case of a more severe disability, arm robots can be used to relearn the impaired movement. Action observation training in real or virtual situations is also effective. Finally, under certain conditions the constraint induced movement therapy is proposed. The effects of rehabilitation are not only positive on the pyramidal symptoms and fatigue but also increase neuroplasticity and perhaps a neuroprotective effect as shown in some studies.
Article
Background: Shoulder subluxation is a frequent complication after stroke causing joint instability, shoulder pain, decreased activities of daily living, and impedance to rehabilitation progress. Electrical stimulation (ES) is considered an effective modality to reduce shoulder subluxation in acute stroke. However, few studies have investigated the effect of position-triggered ES, which induces active muscle contraction though accurate motion detection. Aim: To investigate whether position-triggered ES was more effective in reducing acute hemiplegic shoulder subluxation after stroke than passive ES. Design: Single-blind, randomized controlled trial. Setting: University hospital rehabilitation center. Population: Fifty post-stroke subacute hemiparetic patients with shoulder subluxation. Methods: Patients were randomly assigned into two groups. The position-triggered ES group received 30-minute ES sessions, 5 days per week for 3 weeks with specially modified Novastim® CU-FS1 for motion triggering. The passive ES group received the same protocol without motion triggering. The vertical distance (VD) and the joint distance (JD), relative VD and JD (rVD, rJD), upper extremity component of Fugl-Meyer Motor Assessment (FMAupper), Motricity Index (MI), Manual Function Test (MFT), and peak torque of affected shoulder abductor (PT) were assessed at baseline (T0), end of electrical stimulation session (T1), and 3 weeks (T2) after treatment. Results: Repeated-measures analysis of variance revealed significant interaction between TIME and INTERVENTION on JD and rJD, indicating that shoulder subluxation was significantly more reduced in position-triggered ES than in passive ES (p<0.05). However, FMAupper, MI, MFT, and PT did not show this significance. The change of (Δ)JD , ΔrVD, and ΔrJD in the motion-triggered ES group improved significantly more at T1 than in the passive ES group (p<0.05). This significant improvement was not seen at T2. Conclusions: Position-triggered ES may be more effective than passive ES in improving post-stroke shoulder subluxation; however, this effect was not maintained after the withdrawal of stimulation. Clinical rehabilitation impact: Position-triggered ES may be useful to reducing post-stroke shoulder subluxation.
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Within the perinatal stroke field, there is a need to establish preclinical models where putative biomarkers for motor function can be examined. In a mouse model of perinatal stroke, we evaluated motor map size and movement latency following optogenetic cortical stimulation against three factors of post-stroke biomarker utility: (1) correlation to chronic impairment on a behavioral test battery; (2) amenability to change using a skilled motor training paradigm; and (3) ability to distinguish individuals with potential to respond well to training. Thy1-ChR2-YFP mice received a photothrombotic stroke at postnatal day 7 and were evaluated on a battery of motor tests between days 59 and 70. Following a cranial window implant, mice underwent longitudinal optogenetic motor mapping both before and after 3 weeks of skilled forelimb training. Map size and movement latency of both hemispheres were positively correlated with impaired spontaneous forelimb use, whereas only ipsilesional hemisphere map size was correlated with performance in skilled reaching. Map size and movement latency did not show groupwise changes with training; however, mice with the smallest pretraining map sizes and worst impairments demonstrated the greatest expansion of map size in response to skilled forelimb training. Overall, motor map size showed utility as a potential biomarker for impairment and training-induced modulation in specific individuals. Future assessment of the predictive capacity of post-stroke motor representations for behavioral outcome in animal models opens the possibility of dissecting how plasticity mechanisms contribute to recovery following perinatal stroke.
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Despite an increase in the amount of published stroke recovery research, interventions have failed to markedly affect the trajectory of recovery poststroke. We argue that early-phase research to systematically investigate dose is an important contributor to advance the science underpinning stroke recovery. In this article, we aim to ( a) define the problem of insufficient use of a systematic approach to early-phase, multidimensional dose articulation research and ( b) propose a solution that applies this approach to design a multidimensional phase I trial to identify the maximum tolerated dose (MTD). We put forward a design template as a decision support tool to increase knowledge of how to develop a phase I dose-ranging trial for nonpharmaceutical stroke recovery interventions. This solution has the potential to advance the development of efficacious stroke recovery interventions, which include activity-based rehabilitation interventions.
Chapter
Neuroplasticity follows nervous system injury in the presence or absence of rehabilitative treatments. Rehabilitative interventions can be used to modulate adaptive neuroplasticity, reducing motor impairment and improving activities of daily living in patients with brain lesions. Learning principles guide some rehabilitative interventions. While basic science research has shown that reward combined with training enhances learning, this principle has been only recently explored in the context of neurorehabilitation. Commonly used reinforcers may be more or less rewarding depending on the individual or the context in which the task is performed. Studies in healthy humans showed that both reward and punishment can enhance within-session motor performance; but reward, and not punishment, improves consolidation and retention of motor skills. On the other hand, neurorehabilitative training after brain lesions involves complex tasks (e.g., walking and activities of daily living). The contribution of reward to neurorehabilitation is incompletely understood. Here, we discuss recent research on the role of reward in neurorehabilitation and the needed directions of future research.
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Spinal cord injury (SCI) is a devastating condition that affects approximately 294,000 people in the USA and several millions worldwide. The corticospinal motor circuitry plays a major role in controlling skilled movements and in planning and coordinating movements in mammals and can be damaged by SCI. While axonal regeneration of injured fibers over long distances is scarce in the adult CNS, substantial spontaneous neural reorganization and plasticity in the spared corticospinal motor circuitry has been shown in experimental SCI models, associated with functional recovery. Beneficially harnessing this neuroplasticity of the corticospinal motor circuitry represents a highly promising therapeutic approach for improving locomotor outcomes after SCI. Several different strategies have been used to date for this purpose including neuromodulation (spinal cord/brain stimulation strategies and brain-machine interfaces), rehabilitative training (targeting activity-dependent plasticity), stem cells and biological scaffolds, neuroregenerative/neuroprotective pharmacotherapies, and light-based therapies like photodynamic therapy (PDT) and photobiomodulation (PMBT). This review provides an overview of the spontaneous reorganization and neuroplasticity in the corticospinal motor circuitry after SCI and summarizes the various therapeutic approaches used to beneficially harness this neuroplasticity for functional recovery after SCI in preclinical animal model and clinical human patients’ studies.
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Patients with neurodevelopmental disorders show impaired motor skill learning. It is unclear how the effect of genetic variation on synaptic function and transcriptome profile may underlie experience-dependent cortical plasticity, which supports the development of fine motor skills. RELN (reelin) is one of the genes implicated in neurodevelopmental psychiatric vulnerability. Heterozygous reeler mutant (HRM) mice displayed impairments in reach-to-grasp learning, accompanied by less extensive cortical map reorganization compared with wild-type mice, examined after 10 days of training by intracortical microstimulation. Assessed by patch-clamp recordings after 3 days of training, the training induced synaptic potentiation and increased glutamatergic-transmission of cortical layer III pyramidal neurons in wild-type mice. In contrast, the basal excitatory and inhibitory synaptic functions were depressed, affected both by presynaptic and postsynaptic impairments in HRM mice; and thus, no further training-induced synaptic plasticity occurred. HRM exhibited downregulations of cortical synaptophysin, immediate-early gene expressions, and gene enrichment, in response to 3 days of training compared with trained wild-type mice, shown using quantitative reverse transcription polymerase chain reaction, immunohistochemisty, and RNA-sequencing. We demonstrated that motor learning impairments associated with modified experience-dependent cortical plasticity are at least partially attributed by the basal synaptic alternation as well as the aberrant early experience-induced gene enrichment in HRM.
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Mobility disability is prevalent in aging populations. While existing walking interventions improve aspects related to mobility, meaningful and sustained changes leading to preventing and reversing mobility disability have remained elusive. Split-belt treadmills can be used to train gait adaptability and may be a potential long-term rehabilitation tool for those at risk for mobility decline. As adaptability is necessary for community walking, we investigated the feasibility of a small, randomized controlled 16-week gait adaptability training program in a cohort of 38 sedentary older adults at risk for mobility disability. Individuals were randomly assigned to one of three groups: traditional treadmill training, split-belt treadmill training, or no-contact control. Both treadmill interventions included progressive training 3 days a week, focusing on increasing duration and speed of walking. Cognitive, functional, cardiovascular, and gait assessments were completed before and after the intervention. While individuals were able to complete split-belt treadmill training, only Timed Up and Go performance was significantly improved compared to traditional treadmill training. As the stimulus provided by the split-belt training was difficult to control, we did not observe a clear benefit for split-belt treadmill training over traditional treadmill training. Our findings indicate a cautionary tale about the implementation of complex training interventions.
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The movements of rats trained to reach through an aperture for food pellets, located on a shelf, were videorecorded and filmed from lateral and ventral perspectives for analysis using Eshkol-Wachman Movement Notation (EWMN). Reaching was subdivided into phases of locating the food and advancing the limb to grasp the food, bringing the food to the mouth, and returning to the starting position. Further analysis of the movements comprising these acts revealed a number of novel findings. (1) Most of the first phase of the movement is produced proximally, with the limb lifted, aimed, and advanced from the shoulder. (2) After the limb is lifted from the substrate to initiate reaching, it is carried to a parasagittal position so that the long axis of the forearm is aligned along the midline of the body. This aspect of the movement 'aims' the limb toward the target. (3) The digits are opened as the limb is advanced from the aiming position toward the food. As the paw approaches the food, pronation of the palm is accomplished by abduction of the upper arm. (4) As the limb is retracted, the digits are closed to grasp the food. As retraction ends, the paw is supinated by a rotatory movement at the wrist. This is the only distal rotatory movement. (5) The position taken by the second forelimb, as it is adducted to aid in holding the food pellet for eating, resembles the 'aiming' posture. The results are discussed in reference to the kinematics, neural control, and the evolutionary origins of reaching in the rat and other animals. Additionally, the results provide a framework for analysis of changes in movements produced by physiological manipulations.
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In conclusion, the rat primary motor cortex appears to be organized into irregularly shaped patches of cortex devoted to particular movements. The location of major subdivisions such as the forelimb or hindlimb areas is somatotopic and is consistent from animal to animal, but the internal organization of the pattern of movements represented within major subdivisions varies significantly between animals. The motor cortex includes both agranular primary motor cortex (AgL) and, in addition, a significant amount of the bordering granular somatic sensory cortex (Gr(SI)), as well as the rostral portion of the taste sensory insular or claustrocortex (Cl). The rat frontal cortex also contains a second, rostral motor representation of the forelimb, trunk and hindlimb, which is somatotopically organized and may be the rat's supplementary motor area. Both of these motor representations give rise to direct corticospinal projections, some of which may make monosynaptic connections with cervical enlargement motoneurons. Medial to the primary motor cortex, in cytoarchitectonic field AgM, is what appears to be part of the rat's frontal eye fields, a region which also includes the vibrissae motor representation. The somatic motor cortical output organization pattern in the rat is remarkably similar to that seen in the primate, whose primary, supplementary and frontal eye field cortical motor regions have been extensively studied.
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This study was undertaken to document plastic changes in the functional topography of primary motor cortex (M1) that are generated in motor skill learning in the normal, intact primate. Intracortical microstimulation mapping techniques were used to derive detailed maps of the representation of movements in the distal forelimb zone of M1 of squirrel monkeys, before and after behavioral training on two different tasks that differentially encouraged specific sets of forelimb movements. After training on a small-object retrieval task, which required skilled use of the digits, their evoked-movement digit representations expanded, whereas their evoked-movement wrist/forearm representational zones contracted. These changes were progressive and reversible. In a second motor skill exercise, a monkey pronated and supinated the forearm in a key (eyebolt)-turning task. In this case, the representation of the forearm expanded, whereas the digit representational zones contracted. These results show that M1 is alterable by use throughout the life of an animal. These studies also revealed that after digit training there was an areal expansion of dual-response representations, that is, cortical sectors over which stimulation produced movements about two or more joints. Movement combinations that were used more frequently after training were selectively magnified in their cortical representations. This close correspondence between changes in behavioral performance and electrophysiologically defined motor representations indicates that a neurophysiological correlate of a motor skill resides in M1 for at least several days after acquisition. The finding that cocontracting muscles in the behavior come to be represented together in the cortex argues that, as in sensory cortices, temporal correlations drive emergent changes in distributed motor cortex representations.
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Recent work has suggested that changes in synapse number as well as changes in the expression of the Fos protein may occur within the motor cortex in association with motor learning. The number of synapses per neuron and the percentage of Fos-positive neurons within layer II/III of the rat motor cortex was measured after training on a complex motor learning task. Adult female rats were allocated randomly to either an acrobatic condition (AC), a motor control condition (MC), or an inactive control condition (IC). AC animals were trained to traverse a complex series of obstacles, and each AC animal was pair matched with an MC animal that traversed an obstacle-free runway. IC animals received no motor training. Animals from each condition were killed at various points during training, and unbiased stereological techniques were used to estimate the number of synapses per neuron and the percentage of Fos-positive cells within layer II/III of the motor cortex. AC animals exhibited an overall increase in the number of synapses per neuron in comparison to MC and IC animals at later stages of training. AC animals also had a significantly higher overall percentage of Fos-positive cells in comparison to both controls, with a trend for the increase to be greater during the acquisition versus the maintenance phase. These data suggest that Fos may be involved in the biochemical processes underlying skill acquisition and that motor learning, as opposed to motor activity, leads to increases in synapse number in the motor cortex.
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Complex motor skill learning, but not mere motor activity, leads to an increase in synapse number within the cerebellar cortex. The present experiment used quantitative electron microscopy to determine which synapse types were altered in number. Adult female rats were allocated to either an acrobatic condition (AC), a voluntary exercise condition (VX), or an inactive condition (IC). AC animals were trained to traverse an elevated obstacle course requiring substantial motor coordination to complete. VX animals were housed with unlimited access to running wheels and IC animals received no motor training but were handled briefly each day. Results showed the AC animals to have significantly more parallel fiber to Purkinje cell synapses than both the VX and IC animals. No other synapse type was significantly altered. Thus, the learning-dependent increase in synapse number observed within the cerebellar cortex is accomplished primarily through the addition of parallel fiber synapses.
Article
It is now clear that the motor cortex of adult mammals is capable of widespread functional reorganization. After specific types of motor skill training, the cortical representations of the movements used to perform the task expand, invading adjacent motor representations. After peripheral nerve injury, representations of unaffected muscles expand, invading those of the denervated muscles. After focal cortical injury, representations in the uninjured, adjacent cortical tissue undergo widespread alterations. Specific changes are dependent upon the use of the affected limb during the postinjury period. It now appears likely that motor map alterability results from changes in synaptic efficacy of intrinsic horizontal connections within motor cortex. Taken together, these studies suggest that the neurophysiological circuitry underlying muscle and movement maps within primary motor cortex is continually remodeled throughout an individual's life. The functional organization of motor cortex is constantly reshaped by behavioral demands for the learning of new motor skills.
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Evidence supports the view that 'memory traces' are formed in the hippocampus and in the cerebellum in classical conditioning of discrete behavioural responses. In the hippocampus learning results in long-lasting increases in excitability of pyramidal neurons that resemble the phenomenon of long-term potentiation. Although it plays a role in certain aspects of conditioning, the hippocampus is not necessary for learning and memory of the basic conditioned responses. The cerebellum and its associated brain-stem circuitry, on the other hand, does appear to be essential (necessary and sufficient) for learning and memory of the conditioned response. Evidence to date supports the view that mossy fibre convey conditioned stimulus information and that climbing fibres conveys the critical 'reinforcement' information to the cerebellum and that 'memory traces' appear to be formed in cerebellar cortex and interpositus nucleus.
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The primary motor cortex (MI) contains a map organized so that contralateral limb or facial movements are elicited by electrical stimulation within separate medial to lateral MI regions. Within hours of a peripheral nerve transection in adult rats, movements represented in neighboring MI areas are evoked from the cortical territory of the affected body part. One potential mechanism for reorganization is that adjacent cortical regions expand when preexisting lateral excitatory connections are unmasked by decreased intracortical inhibition. During pharmacological blockade of cortical inhibition in one part of the MI representation, movements of neighboring representations were evoked by stimulation in adjacent MI areas. These results suggest that intracortical connections form a substrate for reorganization of cortical maps and that inhibitory circuits are critically placed to maintain or readjust the form of cortical motor representations.
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Single electrode voltage clamp recordings were made during Pavlovian conditioning of single units of the motor cortex of cats. Units that developed a conditioned spike discharge in response to a click conditioned stimulus (CS) after pairing the click with glabella tap and local ionophoretic application of glutamate showed increases in input resistance and reductions of an early outward current induced by depolarizing commands and by return to holding potentials after hyperpolarizing commands. Changes in later currents were also found in some cells. Units that failed to develop a conditioned response did not show these changes. The decreases in membrane currents could contribute to an increased spike discharge in response to the CS as could the increased input resistance observed after conditioning. Conductance changes of this type may serve as engrams by which some forms of memory and learning are expressed across both vertebrate and invertebrate species.
Article
In order to examine the effects of repetitive stimulation on functional cortical organization, standard intracortical microstimulation (ICMS) techniques were used to generate maps of movement representations in motor cortex of rat. After identification of caudal and rostral forelimb fields and adjacent vibrissae and neck fields, one or more representational borders were defined in greater detail. Then a microelectrode was introduced into one of these representational fields, and ICMS current pulses were delivered at a rate of 1/sec for 1 to 3 hr. Following repetitive ICMS, significant changes in movement representations were observed using current levels that were either suprathreshold or subthreshold for evoking the site-specific movement. Electromyographic activity could be evoked at suprathreshold and near-threshold current levels, but not at the subthreshold current levels used here. Significant border shifts ranged from 210 to 670 microns. In each case in which shifts occurred, there appeared to be expansion of the movement represented at the repetitively stimulated site. The effects were progressive and reversible. These results suggest that at least under these unusual experimental circumstances, large representational changes can be generated very rapidly within motor cortex in the absence of any evident peripheral feedback.
Article
In the accompanying paper (Sanes et al. 1989), we demonstrated that the map of motor cortex (MI) output was reorganized when examined 1 week to 4 months after a motor nerve lesion in adult rats. The present experiments measured the extent of functional reorganization that occurs within the first hours after this lesion. Shifts in MI output were examined by testing the effect of stimulation at a site in MI vibrissa area before and up to 10 h after nerve section of the branches of the facial nerve that innervate the vibrissa. Immediately following nerve transection, no movement or forelimb EMG activity was evoked by intracortical electrical stimulation within the vibrissa area. Within hours of the nerve transection, however, stimulation elicited forelimb EMG responses that were comparable to those obtained by stimulating within the pre-transection forelimb area. Remapping of MI after nerve transection indicated that the forelimb boundary had shifted about 1 mm medially from its original location into the former vibrissa territory. Forelimb EMG could be evoked for up to 10 h within this reorganized cortex. These results indicated that the output circuits of MI can be quickly reorganized by nerve lesions in adult mammals.
Article
The behavioural impairments and subsequent recovery were studied in rats with circumscribed unilateral lesions in the somatic sensorimotor cortex (SMC). Lesions were made in the caudal forelimb region (CFL), the rostral forelimb region (RFL), the anteromedial cortex (AMC) or the hindlimb area. Rats with damage in the CFL produced a deficit in placing the forelimb contralateral to the lesion during exploratory locomotion on a grid surface. Rats with AMC damage circled in the direction ipsilateral to the lesion. Lesions in the CFL or AMC produced an ipsilateral somatosensorimotor asymmetry on the bilateral-stimulation test (responding to adhesive patches placed on the contralateral forelimb was slower) that recovered in 7 days following AMC lesions or 28 days following CFL lesions. Finally, RFL lesions produced an ipsilateral asymmetry on the bilateral-stimulation task that was more severe and enduring (recovery in 60 days). After behavioral recovery, the effects of an additional lesion placed in the homotopic contralateral cortex were examined (two-stage bilateral lesion). Rats receiving two-stage bilateral lesions in the RFL or CFL responded slower to tactile stimulation of the forelimb contralateral to the second lesion. In the case of CFL-damaged rats, placing deficits also appeared contralateral to the most recent injury. In contrast, rats receiving two-stage bilateral AMC lesions did not exhibit behavioral asymmetries following the second lesion. These results provide evidence to suggest that subdivisions of the rat SMC can be distinguished with lesion/behavioral experiments. Moreover, a comparison of the effects of unilateral and two-stage bilateral lesions may help in the parcellation of the rat SMC into functionally distinct subareas and provide a basis for studying the processes of recovery and maintenance of function following brain damage.
Article
Effects of motor training on a neocortical nerve cell population involved in performance of the motor task were assessed by measuring Layer V pyramidal neuron apical dendritic branching in motor-sensory forelimb cortex of rats trained to reach into a tube for food. Rats were trained to reach with the forepaw they preferred to use (group PRAC), the nonpreferred forepaw (REV), both forepaws (ALT), or neither forepaw (CONT). Across groups, hemispheres opposite trained forepaws had larger apical dendritic fields, in terms of total dendritic length, number of oblique branches from the apical shaft, and length of terminal branches. Similar, although somewhat less consistent, effects were seen when results were analyzed for between- (CONT vs ALT) and within-subject comparisons (trained vs nontrained hemispheres of REV and PRAC). This finding is compatible with the hypothesis that altered dendritic patterns, with associated synapses, are involved in storage of information from the training experience. The within-subject effects mitigate suggestions that these differences arise from generally acting hormonal or metabolic consequences of the training experience, although the possibility that these effects result from neural activity per se and are unrelated to information storage cannot be excluded.
Article
We have previously reported that training rats to reach for bits of cookies resulted in an increase in dendritic length and branching complexity in the apical branches of layer V pyramidal cells within the motor-sensory forelimb cortex. In this paper, we describe the effects of reach training upon the basilar branches of two subpopulations of pyramidal cells in layers II and III. The two subpopulations of pyramids are distinguishable by morphological characteristics and location within layers II and III. The basilar dendrites of one subtype, the forked apical pyramid, are selectively altered in size and complexity during reach training; whereas the other subtype, the single shaft apical cells, do not measurably change during training. Based upon these findings, we postulate that these cells may have different roles in governing the reaching behavior.
Article
The vestibulo-ocular reflex (VOR) stabilizes retinal images by generating smooth eye movements that are equal in amplitude and opposite in direction to head turns. Whenever image motion occurs persistently during head turns, the VOR undergoes motor learning; as a result image stability is gradually restored. A group of brain stem neurons that are in the modified pathways has now been described. The neurons express changes in firing in association with motor learning in the VOR and receive monosynaptic inhibition from the flocculus of the cerebellum. The changes in firing have an appropriate magnitude and are expressed at the correct latency to account for the altered VOR. The response properties of the neurons point to their brain stem vestibular inputs for further investigation of the site of motor learning.
Article
The sensory properties of neurons in the several forelimb areas of rat sensorimotor cortex were examined using the technique of extracellular single-unit recording in the awake, head-restrained rat. Cells with peripheral receptive fields were tested for the amount and modality of sensory input during joint manipulation and brushing and tapping of limbs, face and trunk. Input-output correlations were made on the basis of the results of receptive field mapping and intracortical microstimulation in the same electrode penetration. It was found that neurons (n = 117) in the rostral forelimb area receive virtually no sensory input while 30% of neurons (n = 114) in the caudal forelimb primary motor area do receive such input. The inputs to caudal forelimb motor area neurons were primarily (83%) from single joints; along perpendicular electrode penetrations the same joint that activated a cortical cell also moved when microstimulation was delivered along the same electrode penetration. In the granular and dysgranular zones of somatic sensory forelimb cortex, 70% of neurons (n = 82) were responsive to peripheral sensory inputs, with most of the cells in the granular cortex responsive to cutaneous inputs while cells in the dysgranular cortex were more responsive to deep inputs. The lack of sensory inputs to the rostral forelimb motor area is consistent with the proposal that this region may be a part of the supplementary motor area of the rat.
Article
Features of neuronal activity in two subdivisions of primary motor cortex (MI) were recorded in awake rats. Neurons in the caudal part of MI, which overlaps part of the somatic sensory cortex, discharge with brief bursts in conjunction with isometric bar pressing with the forelimb. Cells in this caudal region are activated by cutaneous stimuli. In the rostral part of MI, neurons discharge prior to and during forelimb force changes, begin to discharge earlier than in the caudal zone, and have non-cutaneous or unidentifiable receptive fields. These results suggest separate motor control functions for rostral and caudal parts of rat MI.
Article
The ability of rats to perform a discrete digital task after cortical lesions was studied. Six out of 8 rats with bilateral, frontal cortex ablation demonstrated a large drop in performance levels which persisted througout the 3 month testing period. Animals with occipital cortex lesions showed no postoperative drop in performance.
Article
Intracortical microstimulation of 40--50 points in the frontal cortex of ketamine-anesthetized rats using perpendicular penetrations has demonstrated a second forelimb area located rostrally near the frontal pole as well as confirming the existence of a more caudally located forelimb area just anterior to bregma. Cortex where neck and/or vibrissae movements were evoked separated the two forelimb areas. The rostral and caudal forelimb areas defined by microstimulation correspond with patches of corticospinal neurons labeled with HRP following injections of this tracer into the cervical enlargement. Digit movements were commonly evoked from the rostral forelimb area but were rarely elicited from the caudal forelimb area. The question of whether the rostral forelimb region is part of primary or supplementary motor cortex is not yet able to be answered.
Article
Two force transducers which were interfaced with a minicomputer were used as operant manipulanda to assess changes in peak force and rate of response produced by unilateral motor cortical lesions in rats. Spatial arrangement of the manipulanda permitted a subject to respond on Transducer I exclusively with his left forepaw and on Transducer II exclusively with his right. Permanent deficits as measured by both force and rate of response were observed for the limb contralateral to the lesion. In the forelimb ipsilateral to the lesion rate of response was severely depressed immediately following the lesion and, although there was marked recovery during the 10-12 days following surgery, post-lesion rates never attained pre-lesion levels.
Article
Although it was once thought that the corticospinal (pyramidal) tract was the main substrate of voluntary movement, the extent to which it is involved in the control of proximal vs. distal musculature, independent finger movements, and movements characteristic of different species of animals now is unclear. The objective of this study was to examine the effects of pyramidal tract lesions on skilled forelimb use in rats. In addition, cell morphology in motor cortex following lesions was examined. Naive and trained rats received unilateral pyramidal sections just rostral to the pyramidal decussation. Performance was assessed and filmed on two reaching tasks. Measures of reaching consisted of success in obtaining food, kinematic analysis of limb trajectory and velocity, and qualitative evaluation of 10 movement components comprising a reach. Pyramidal tract lesions only impaired reaching for single food pellets. Almost all movements comprising a reach, except digit opening, were impaired, including lifting, aiming, pronating and supinating the limb, and releasing food. Although success in limb use was unchanged over the 180 day observation period, there were significant improvements in the qualitative features of limb use. Histologically, the morphology of pyramidal cells in the forelimb area ipsilateral to the lesion seemed normal. Rats with additional damage to adjacent structures, such as the medial lemniscus and olivary complex, were much more severely impaired on the reaching tasks, and displayed similar impairments as judged by qualitative and kinematic measures. The results demonstrate that a number of movements involved in independent limb use are chronically impaired by pyramidal tract lesions in the rat. Nevertheless, significant use of the limb is possible, due perhaps to both the contribution of extrapyramidal motor systems and the influence of the remaining pyramidal system through its extrapyramidal connections. The results not only show that the rat pyramidal tract supports functions very similar to those of primates and thus might provide a good model for some aspects of pyramidal tract dysfunctions, but also they argue that the pyramidal tract is involved in both proximal and distal limb movements.
Article
The existence of multiple motor cortical areas that differ in some of their properties is well known in primates, but is less clear in the rat. The present study addressed this question from the point of view of connectional properties by comparing the afferent and efferent projections of the caudal forelimb area (CFA), considered to be the equivalent of the forelimb area of the primary motor cortex (MI), and a second forelimb motor representation, the rostral forelimb area (RFA). As a result of various tracing experiments (including double labeling), it was observed that CFA and RFA had reciprocal corticocortical connections characterized by preferential, asymmetrical, laminar distribution, indicating that RFA may occupy a different hierarchical level than CFA, according to criteria previously discussed in the visual cortex of primates. Furthermore, it was found that RFA, but not CFA, exhibited dense reciprocal connections with the insular cortex. With respect to their efferent projection to the basal ganglia, it was observed that CFA projected very densely to the lateral portion of the ipsilateral caudate putamen, whereas the contralateral projection was sparse and more restricted. The ipsilateral projection originating from RFA was slightly less dense than that from CFA, but it covered a larger portion of the caudate putamen (in the medial direction); the contralateral projection from RFA to the caudate putamen was of the same density and extent as the ipsilateral projection. The reciprocal thalamocortical and corticothalamic connections of RFA and CFA differed from each other in the sense that CFA was mainly interconnected with the ventrolateral thalamic nucleus, while RFA was mainly connected with the ventromedial thalamic nucleus. Altogether, these connectional differences, compared with the pattern of organization of the motor cortical areas in primates, suggest that RFA in the rat may well be an equivalent of the premotor or supplementary motor area. In contrast to the corticocortical, corticostriatal, and thalamocortical connections, RFA and CFA showed similar efferent projections to the subthalamic nucleus, substantia nigra, red nucleus, tectum, pontine nuclei, inferior olive, and spinal cord.
Article
We mapped movement representations in motor cortex of rats that had their mystacial vibrissae (whiskers) clipped continually for various periods during their development. In animals clipped since birth, and in adult animals clipped for 5 days, there was a significant reduction in the ratio of whisker to forelimb representation areas. Allowing the whiskers to regrow for at least 72 h resulted in normal-appearing representation patterns. The plasticity of motor representations induced by whisker clipping, and that following whisker regrowth, were not age dependent. These findings indicate that a relatively innocuous procedure that restricts sensory and motor functions results in pronounced, and reversible, changes in the functional organization of the motor cortex.
Article
This study investigates the influence of early somatosensory experience on shaping movement representation patterns in motor cortex. Electrical microstimulation was used to map bilaterally the motor cortices of adult rats subjected to altered tactile experience by unilateral vibrissa trimming from birth (birth-trimmed group) or for comparable periods that began in adulthood (adult-trimmed group). Findings demonstrated that (1) vibrissa trimming from birth, but not when initiated in adulthood, led to a significantly smaller-sized primary motor cortex (M1) vibrissa representation in the hemisphere contralateral to the trimmed vibrissae, with no evidence for concomitant changes in size of the adjacent forelimb representation or the representation of the intact vibrissae in the opposite (ipsilateral) hemisphere; (2) in the contralateral hemispheres of the birth-trimmed group, an abnormal pattern of evoked vibrissa movement was evident in which bilateral or ipsilateral (intact) vibrissa movement predominated; (3) in both hemispheres of the birth-trimmed group, current thresholds for eliciting movement of the trimmed vibrissa were significantly lower than normal; and (4) in the adult-trimmed group, but not in the birth-trimmed group, there was a decrease bilaterally in the relative frequency of dual forelimb-vibrissa sites that form the common border between these representations. These results show that sensory experience early in life exerts a significant influence in sculpting motor representation patterns in M1. The mature motor cortex is more resistant to the type and magnitude of influence that tactile experience has on developing M1, which may indicate that such an influence is constrained by a developmentally regulated critical period.
Integrative and Molecular Approaches to Brain Function, edited by Use-dependent alterations of movement representations in primary motor cortex of adult squirrel monkeys
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