Upper Limb Sensory-Motor Control During Exposure to Different Mechanical Environments in Multiple Sclerosis Subjects With No Clinical Disability.

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease resulting in motor impairments associated with muscle weakness and lack of movement coordination. The goal of this work was to quantify upper limb motor deficits in asymptomatic MS subjects with a robot-based assessment including performance and muscle synergies analysis. A total of 7 subjects (MS: 3 M-4 F; 42 ± 10 years) with clinically definite MS according to McDonald criteria, but with no clinical disability, and 7 age- and sex-matched subjects without a history of neurological disorders participated in the study. All subjects controlled a cursor on the computer screen by moving their hand or applying forces in 8 coplanar directions at their self-selected speed. They grasped the handle of a robotic planar manipulandum that generated four different environments: null, assistive or resistive forces, and rigid constraint. Simultaneously, the activity of 15 upper body muscles was recorded. Asymptomatic MS subjects generated less smooth and less accurate cursor trajectories than control subjects in controlling a force profile, while the end-point error was significantly different also in the other environments. The EMG analysis revealed different muscle activation patterns in MS subjects when exerting isometric forces or when moving in presence of external forces generated by a robot. While the two populations had the same number and similar structure of muscle synergies, they had different activation profiles. These results suggested that a task requiring to control forces against a rigid environment allows better than movement tasks to detect early sensory-motor signs related to the onset of symptoms of multiple sclerosis and to differentiate between stages of the disease.

A Novel Patient-Tailored, Cumulative Neurotechnology-Based Therapy for Upper-Limb Rehabilitation in Severely Impaired Chronic Stroke Patients: The AVANCER Study Protocol.

Effective, patient-tailored rehabilitation to restore upper-limb motor function in severely impaired stroke patients is still missing. If suitably combined and administered in a personalized fashion, neurotechnologies offer a large potential to assist rehabilitative therapies to enhance individual treatment effects. AVANCER (clinicaltrials.gov NCT04448483) is a two-center proof-of-concept trial with an individual based cumulative longitudinal intervention design aiming at reducing upper-limb motor impairment in severely affected stroke patients with the help of multiple neurotechnologies. AVANCER will determine feasibility, safety, and effectivity of this innovative intervention. Thirty chronic stroke patients with a Fugl-Meyer assessment of the upper limb (FM-UE) <20 will be recruited at two centers. All patients will undergo the cumulative personalized intervention within two phases: the first uses an EEG-based brain-computer interface to trigger a variety of patient-tailored movements supported by multi-channel functional electrical stimulation in combination with a hand exoskeleton. This phase will be continued until patients do not improve anymore according to a quantitative threshold based on the FM-UE. The second interventional phase will add non-invasive brain stimulation by means of anodal transcranial direct current stimulation to the motor cortex to the initial approach. Each phase will last for a minimum of 11 sessions. Clinical and multimodal assessments are longitudinally acquired, before the first interventional phase, at the switch to the second interventional phase and at the end of the second interventional phase. The primary outcome measure is the 66-point FM-UE, a significant improvement of at least four points is hypothesized and considered clinically relevant. Several clinical and system neuroscience secondary outcome measures are additionally evaluated. AVANCER aims to provide evidence for a safe, effective, personalized, adjuvant treatment for patients with severe upper-extremity impairment for whom to date there is no efficient treatment available.

Stroke impairs the control of isometric forces and muscle activations in the ipsilesional arm.

Stroke often impairs the control of the contralesional arm, thus most survivors rely on the ipsilesional arm to perform daily living activities that require an efficient control of movements and forces. Whereas the ipsilesional arm is often called 'unaffected' or 'unimpaired', several studies suggested that during dynamic tasks its kinematics and joint torques are altered. Is stroke also affecting the ability of the ipsilesional arm to produce isometric force, as when pushing or pulling a handle? Here, we address this question by analyzing behavioral performance and muscles' activity when subjects applied an isometric force of 10 N in eight coplanar directions. We found that stroke affected the ability to apply well-controlled isometric forces with the ipsilesional arm, although to a minor extent compared to the contralesional arm. The spinal maps, the analysis of single muscle activities and the organization of muscle synergies highlighted that this effect was mainly associated with abnormal activity of proximal muscles with respect to matched controls, especially when pushing or pulling in lateral directions.

Effects of Hemispheric Stroke Localization on the Reorganization of Arm Movements within Different Mechanical Environments.

This study investigated how stroke's hemispheric localization affects motor performance, spinal maps and muscle synergies while performing planar reaching with and without assistive or resistive forces. A lesion of the right hemisphere affected performance, reducing average speed and smoothness and augmenting lateral deviation in both arms. Instead, a lesion of the left hemisphere affected the aiming error, impairing the feedforward control of the ipsilesional arm. The structure of the muscle synergies had alterations dependent on the lesion side in both arms. The applied force fields reduced the differences in performance and in muscle activations between arms and among populations. These results support the hypotheses of hemispheric specialization in movement control and identify potential significant biomarkers for the design of more effective and personalized rehabilitation protocols.

A multimodal approach to capture post-stroke temporal dynamics of recovery.

OBJECTIVE: Several training programs have been developed in the past to restore motor functions after stroke. Their efficacy strongly relies on the possibility to assess individual levels of impairment and recovery rate. However, commonly used clinical scales rely mainly on subjective functional assessments and are not able to provide a complete description of patients' neuro-biomechanical status. Therefore, current clinical tests should be integrated with specific physiological measurements, i.e. kinematic, muscular, and brain activities, to obtain a deep understanding of patients' condition and of its evolution through time and rehabilitative intervention. APPROACH: We proposed a multivariate approach for motor control assessment that simultaneously measures kinematic, muscle and brain activity and combines the main physiological variables extracted from these signals using principal component analysis (PCA). We tested it in a group of six sub-acute stroke subjects evaluated extensively before and after a four-week training, using an upper-limb exoskeleton while performing a reaching task, along with brain and muscle measurements. MAIN RESULTS: After training, all subjects exhibited clinical improvements correlating with changes in kinematics, muscle synergies, and spinal maps. Movements were smoother and faster, while muscle synergies increased in numbers and became more similar to those of the healthy controls. These findings were coupled with changes in cortical oscillations depicted by EEG-topographies. When combining these physiological variables using PCA, we found that (i) patients' kinematic and spinal maps parameters improved continuously during the four assessments; (ii) muscle coordination augmented mainly during treatment, and (iii) brain oscillations recovered mostly pre-treatment as a consequence of short-term subacute changes. SIGNIFICANCE: Although these are preliminary results, the proposed approach has the potential of identifying significant biomarkers for patient stratification as well as for the design of more effective rehabilitation protocols.

Motor improvement estimation and task adaptation for personalized robot-aided therapy: a feasibility study.

BACKGROUND: In the past years, robotic systems have become increasingly popular in upper limb rehabilitation. Nevertheless, clinical studies have so far not been able to confirm superior efficacy of robotic therapy over conventional methods. The personalization of robot-aided therapy according to the patients' individual motor deficits has been suggested as a pivotal step to improve the clinical outcome of such approaches. METHODS: Here, we present a model-based approach to personalize robot-aided rehabilitation therapy within training sessions. The proposed method combines the information from different motor performance measures recorded from the robot to continuously estimate patients' motor improvement for a series of point-to-point reaching movements in different directions. Additionally, it comprises a personalization routine to automatically adapt the rehabilitation training. We engineered our approach using an upper-limb exoskeleton. The implementation was tested with 17 healthy subjects, who underwent a motor-adaptation paradigm, and two subacute stroke patients, exhibiting different degrees of motor impairment, who participated in a pilot test undergoing rehabilitative motor training. RESULTS: The results of the exploratory study with healthy subjects showed that the participants divided into fast and slow adapters. The model was able to correctly estimate distinct motor improvement progressions between the two groups of participants while proposing individual training protocols. For the two pilot patients, an analysis of the selected motor performance measures showed that both patients were able to retain the improvements gained during training when reaching movements were reintroduced at a later stage. These results suggest that the automated training adaptation was appropriately timed and specifically tailored to the abilities of each individual. CONCLUSIONS: The results of our exploratory study demonstrated the feasibility of the proposed model-based approach for the personalization of robot-aided rehabilitation therapy. The pilot test with two subacute stroke patients further supported our approach, while providing encouraging results for the applicability in clinical settings. Trial registration This study is registered in ClinicalTrials.gov (NCT02770300, registered 30 March 2016, https://clinicaltrials.gov/ct2/show/NCT02770300).

Muscle activities in similar arms performing identical tasks reveal the neural basis of muscle synergies.

Are the muscle synergies extracted from multiple electromyographic signals an expression of neural information processing, or rather a by-product of mechanical and task constraints? To address this question, we asked 41 right-handed adults to perform a variety of motor tasks with their left and right arms. The analysis of the muscle activities resulted in the identification of synergies whose activation was different for the two sides. In particular, tasks involving the control of isometric forces resulted in larger differences. As the two arms essentially have identical biomechanical structure, we concluded that the differences observed in the activation of the respective synergies must be attributed to neural control.

Neurotechnology-aided interventions for upper limb motor rehabilitation in severe chronic stroke.

Upper limb motor deficits in severe stroke survivors often remain unresolved over extended time periods. Novel neurotechnologies have the potential to significantly support upper limb motor restoration in severely impaired stroke individuals. Here, we review recent controlled clinical studies and reviews focusing on the mechanisms of action and effectiveness of single and combined technology-aided interventions for upper limb motor rehabilitation after stroke, including robotics, muscular electrical stimulation, brain stimulation and brain computer/machine interfaces. We aim at identifying possible guidance for the optimal use of these new technologies to enhance upper limb motor recovery especially in severe chronic stroke patients. We found that the current literature does not provide enough evidence to support strict guidelines, because of the variability of the procedures for each intervention and of the heterogeneity of the stroke population. The present results confirm that neurotechnology-aided upper limb rehabilitation is promising for severe chronic stroke patients, but the combination of interventions often lacks understanding of single intervention mechanisms of action, which may not reflect the summation of single intervention's effectiveness. Stroke rehabilitation is a long and complex process, and one single intervention administrated in a short time interval cannot have a large impact for motor recovery, especially in severely impaired patients. To design personalized interventions combining or proposing different interventions in sequence, it is necessary to have an excellent understanding of the mechanisms determining the effectiveness of a single treatment in this heterogeneous population of stroke patients. We encourage the identification of objective biomarkers for stroke recovery for patients' stratification and to tailor treatments. Furthermore, the advantage of longitudinal personalized trial designs compared to classical double-blind placebo-controlled clinical trials as the basis for precise personalized stroke rehabilitation medicine is discussed. Finally, we also promote the necessary conceptual change from 'one-suits-all' treatments within in-patient clinical rehabilitation set-ups towards personalized home-based treatment strategies, by adopting novel technologies merging rehabilitation and motor assistance, including implantable ones.

Data-driven body-machine interface for the accurate control of drones.

The accurate teleoperation of robotic devices requires simple, yet intuitive and reliable control interfaces. However, current human-machine interfaces (HMIs) often fail to fulfill these characteristics, leading to systems requiring an intensive practice to reach a sufficient operation expertise. Here, we present a systematic methodology to identify the spontaneous gesture-based interaction strategies of naive individuals with a distant device, and to exploit this information to develop a data-driven body-machine interface (BoMI) to efficiently control this device. We applied this approach to the specific case of drone steering and derived a simple control method relying on upper-body motion. The identified BoMI allowed participants with no prior experience to rapidly master the control of both simulated and real drones, outperforming joystick users, and comparing with the control ability reached by participants using the bird-like flight simulator Birdly.

How are Muscle Synergies Affected by Electromyography Pre-Processing?

Muscle synergies have been used for decades to explain a variety of motor behaviors, both in humans and animals and, more recently, to steer rehabilitation strategies. However, many sources of variability such as factorization algorithms, criteria for dimensionality reduction and data pre-processing constitute a major obstacle to the successful comparison of the results obtained by different research groups. Starting from the canonical EMG processing we determined how variations in filter cut-off frequencies and normalization methods, commonly found in literature, affect synergy weights and inter-subject similarity (ISS) using experimental data related to a 15-muscles upper-limb reaching task. Synergy weights were not significantly altered by either normalization (maximum voluntary contraction - MVC - or maximum amplitude of the signal - SELF) or band-pass filter ([20-500 Hz] or [50-500] Hz). Normalization did, however, alter the amount of variance explained by a set of synergies, which is a criterion often used for model order selection. Comparing different low-pass (LP) filters (0.5 Hz, 4 Hz, 10 Hz, 20 Hz cut-offs) we showed that increasing the low pass filter cut-off had the effect of decreasing the variance accounted for by a set number of synergies and affected individual muscle contributions. Extreme smoothing (i.e., LP cut-off 0.5 Hz) enhanced the contrast between active and inactive muscles but had an unpredictable effect on the ISS. The results presented here constitute a further step towards a thoughtful EMG pre-processing for the extraction of muscle synergies.

Evaluating upper limb impairments in multiple sclerosis by exposure to different mechanical environments.

Multiple sclerosis is a chronic, autoimmune and neurodegenerative disease affecting multiple functional systems and resulting in motor impairments associated with muscle weakness and lack of movement coordination. We quantified upper limb motor deficits with a robot-based assessment including behavioral and muscle synergy analysis in 11 multiple sclerosis subjects with mild to moderate upper limb impairment (9 female; 50 ± 10 years) compared to 11 age- and gender- matched controls (9 female; 50 ± 9 years). All subjects performed planar reaching tasks by moving their upper limb or applying force while grasping the handle of a robotic manipulandum that generated four different environments: free space, assistive or resistive forces, and rigid constraint. We recorded the activity of 15 upper body muscles. Multiple sclerosis subjects generated irregular trajectories. While activities in isolated arm muscles appeared generally normal, shoulder muscle coordination with arm motions was impaired and there was a marked co-activation of the biceps and triceps in extension movements. Systematic differences in timing and organization of muscle synergies have also been observed. This study supports the definition of new biomarkers and rehabilitative treatments for improving upper limb motor coordination in multiple sclerosis.

EEG topographies provide subject-specific correlates of motor control.

Electroencephalography (EEG) of brain activity can be represented in terms of dynamically changing topographies (microstates). Notably, spontaneous brain activity recorded at rest can be characterized by four distinctive topographies. Despite their well-established role during resting state, their implication in the generation of motor behavior is debated. Evidence of such a functional role of spontaneous brain activity would provide support for the design of novel and sensitive biomarkers in neurological disorders. Here we examined whether and to what extent intrinsic brain activity contributes and plays a functional role during natural motor behaviors. For this we first extracted subject-specific EEG microstates and muscle synergies during reaching-and-grasping movements in healthy volunteers. We show that, in every subject, well-known resting-state microstates persist during movement execution with similar topographies and temporal characteristics, but are supplemented by novel task-related microstates. We then show that the subject-specific microstates' dynamical organization correlates with the activation of muscle synergies and can be used to decode individual grasping movements with high accuracy. These findings provide first evidence that spontaneous brain activity encodes detailed information about motor control, offering as such the prospect of a novel tool for the definition of subject-specific biomarkers of brain plasticity and recovery in neuro-motor disorders.

Evaluation of the effects of the Arm Light Exoskeleton on movement execution and muscle activities: a pilot study on healthy subjects.

BACKGROUND: Exoskeletons for lower and upper extremities have been introduced in neurorehabilitation because they can guide the patient's limb following its anatomy, covering many degrees of freedom and most of its natural workspace, and allowing the control of the articular joints. The aims of this study were to evaluate the possible use of a novel exoskeleton, the Arm Light Exoskeleton (ALEx), for robot-aided neurorehabilitation and to investigate the effects of some rehabilitative strategies adopted in robot-assisted training. METHODS: We studied movement execution and muscle activities of 16 upper limb muscles in six healthy subjects, focusing on end-effector and joint kinematics, muscle synergies, and spinal maps. The subjects performed three dimensional point-to-point reaching movements, without and with the exoskeleton in different assistive modalities and control strategies. RESULTS: The results showed that ALEx supported the upper limb in all modalities and control strategies: it reduced the muscular activity of the shoulder's abductors and it increased the activity of the elbow flexors. The different assistive modalities favored kinematics and muscle coordination similar to natural movements, but the muscle activity during the movements assisted by the exoskeleton was reduced with respect to the movements actively performed by the subjects. Moreover, natural trajectories recorded from the movements actively performed by the subjects seemed to promote an activity of muscles and spinal circuitries more similar to the natural one. CONCLUSIONS: The preliminary analysis on healthy subjects supported the use of ALEx for post-stroke upper limb robotic assisted rehabilitation, and it provided clues on the effects of different rehabilitative strategies on movement and muscle coordination.

Muscle synergies and spinal maps are sensitive to the asymmetry induced by a unilateral stroke.

BACKGROUND: Previous studies have shown that a cerebrovascular accident disrupts the coordinated control of leg muscles during locomotion inducing asymmetric gait patterns. However, the ability of muscle synergies and spinal maps to reflect the redistribution of the workload between legs after the trauma has not been investigated so far. METHODS: To investigate this issue, twelve post-stroke and ten healthy participants were asked to walk on a treadmill at controlled speeds (0.5, 0.7, 0.9, 1.1 km/h), while the EMG activity of twelve leg muscles was recorded on both legs. The synergies underlying muscle activation and the estimated motoneuronal activity in the lumbosacral enlargement (L2-S2) were computed and compared between groups. RESULTS: Results showed that muscle synergies in the unaffected limb were significantly more comparable to those of the healthy control group than the ones in the affected side. Spinal maps were dissimilar between the affected and unaffected sides highlighting a significant shift of the foci of the activity toward the upper levels of the spinal cord in the unaffected leg. CONCLUSIONS: Muscle synergies and spinal maps reflect the asymmetry as a motor deficit after stroke. However, further investigations are required to support or reject the hypothesis that the altered muscular organization highlighted by muscle synergies and spinal maps may be due to the concomitant contribution of the altered information coming from the upper part of the CNS, as resulting from the stroke, and to the abnormal sensory feedback due to the neuromuscular adaptation of the patients.

The effect of arm weight support on upper limb muscle synergies during reaching movements.

BACKGROUND: Compensating for the effect of gravity by providing arm-weight support (WS) is a technique often utilized in the rehabilitation of patients with neurological conditions such as stroke to facilitate the performance of arm movements during therapy. Although it has been shown that, in healthy subjects as well as in stroke survivors, the use of arm WS during the performance of reaching movements leads to a general reduction, as expected, in the level of activation of upper limb muscles, the effects of different levels of WS on the characteristics of the kinematics of motion and of the activity of upper limb muscles have not been thoroughly investigated before. METHODS: In this study, we systematically assessed the characteristics of the kinematics of motion and of the activity of 14 upper limb muscles in a group of 9 healthy subjects who performed 3-D arm reaching movements while provided with different levels of arm WS. We studied the hand trajectory and the trunk, shoulder, and elbow joint angular displacement trajectories for different levels of arm WS. Besides, we analyzed the amplitude of the surface electromyographic (EMG) data collected from upper limb muscles and investigated patterns of coordination via the analysis of muscle synergies. RESULTS: The characteristics of the kinematics of motion varied across WS conditions but did not show distinct trends with the level of arm WS. The level of activation of upper limb muscles generally decreased, as expected, with the increase in arm WS. The same eight muscle synergies were identified in all WS conditions. Their level of activation depended on the provided level of arm WS. CONCLUSIONS: The analysis of muscle synergies allowed us to identify a modular organization underlying the generation of arm reaching movements that appears to be invariant to the level of arm WS. The results of this study provide a normative dataset for the assessment of the effects of the level of arm WS on muscle synergies in stroke survivors and other patients who could benefit from upper limb rehabilitation with arm WS.

Effects of early and intensive neuro-rehabilitative treatment on muscle synergies in acute post-stroke patients: a pilot study.

BACKGROUND: After a stroke, patients show significant modifications of neural control of movement, such as abnormal muscle co-activation, and reduced selectivity and modulation of muscle activity. Nonetheless, results reported in literature do not allow to unequivocally explain whether and, in case, how a cerebrovascular accident affects muscle synergies underlying the control of the upper limb. These discrepancies suggest that a complete understanding of the modular re-organization of muscle activity due to a stroke is still lacking. This pilot study aimed at investigating the effects of the conjunction between the natural ongoing of the pathology and the intense robot-mediated treatment on muscle synergies of the paretic upper limb of subacute post-stroke patients. METHODS: Six subacute patients, homogenous with respect to the age and the time elapsed from the trauma, and ten healthy age-matched subjects were enrolled. The protocol consisted in achieving planar movement of the upper limb while handling the end-effector of a robotic platform. Patients underwent 6 weeks long treatment while clinical scores, kinematics of the end-effector and muscle activity were recorded. Then we verified whether muscle coordination underlying the motor task was significantly affected by the cerebrovascular accident and how muscle synergies were modified along the treatment. RESULTS: Results show that although muscle synergies in subacute stroke patients were qualitatively comparable to those of healthy subjects, those underlying the movement of the shoulder can reflect the functional deficit induced by the pathology. Moreover, the improvement of motor performance due to the treatment was achieved in conjunction with slight modifications of muscle synergies. In this regard, modifications of muscle synergies appeared to be influenced by the different recovering mechanisms across patients presumably due to the heterogeneity of lesions, sides and location of the accident. CONCLUSIONS: The results support the hypothesis that muscle synergies reflect the injury of the cerebrovascular accident and could document the effects of the functional recovery due to a suitable and customized treatment. Therefore, they open up new possibilities for the development of more effective neuro-rehabilitation protocols.

Design and evaluation of NEUROBike: a neurorehabilitative platform for bedridden post-stroke patients.

Over the past decades, a large number of robotic platforms have been developed which provide rehabilitative treatments aimed at recovering walking abilities in post-stroke patients. Unfortunately, they do not significantly influence patients' performance after three months from the accident. One of the main reasons underlying this result seems to be related to the time of intervention. Specifically, although experimental evidences suggest that early (i.e., first days after the injury) and intense neuro-rehabilitative treatments can significantly favor the functional recovery of post-stroke patients, robots require patients to be verticalized. Consequently, this does not allow them to be treated immediately after the trauma. This paper introduces a new robotic platform, named NEUROBike, designed to provide neuro-rehabilitative treatments to bedridden patients. It was designed to provide an early and well-addressed rehabilitation therapy, in terms of kinesiology, efforts, and fatigue, accounting for exercises functionally related to daily motor tasks. For this purpose, kinematic models of leg-joint angular excursions during both walking and sit-to-stand were developed and implemented in control algorithms leading both passive and active exercises. Finally, a set of pilot tests was carried out to evaluate the performance of the robotic platform on healthy subjects.

Computational aspects of MN activity estimation: a case study with post-stroke subjects.

Spinal circuits play an important role in the generation of rhythmic motor activity, intermediating between descending signals and peripheral sensory information. The study of these circuits can provide a better understanding of the control mechanisms during the execution of cyclic motor tasks in healthy subjects or in patients with motor deficits due to a neurological disease. This work shows preliminary results regarding the estimation of spinal cord activity of post-stroke subjects obtained from the EMG signals by improving the computational model. This new model allows a better quantitative evaluation of motor performance in clinical contexts.