TYPE Review PUBLISHED 19 July 2022 DOI 10.3389/fneur.2022.939748 Time to reconcile research OPEN ACCESS findings and clinical practice on upper limb neurorehabilitation EDITED BY Mariella Pazzaglia, Sapienza University of Rome, Italy REVIEWED BY Jonathan Sanching Tsay, Leonardo Boccuni1,2,3*, Lucio Marinelli4,5 , Carlo Trompetto4,6 , University of California, Berkeley, United States Alvaro Pascual-Leone1,7,8 and José María Tormos Muñoz1,2,3 Andrea Manca, 1 University of Sassari, Italy Institut Guttmann, Institut Universitari de Neurorehabilitació adscrit a la UAB, Badalona, Spain, 2 Universitat Autònoma de Barcelona, Bellaterra, Spain, 3 Fundació Institut d’Investigació en Ciències *CORRESPONDENCE de la Salut Germans Trias i Pujol, Badalona, Spain, 4 Department of Neuroscience, Rehabilitation, Leonardo Boccuni Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy, 5 IRCCS lboccuni@guttmann.com Ospedale Policlinico San Martino, Department of Neuroscience, Division of Clinical SPECIALTY SECTION Neurophysiology, Genova, Italy, 6 IRCCS Ospedale Policlinico San Martino, Department of This article was submitted to Neuroscience, Division of Neurorehabilitation, Genova, Italy, 7 Hinda and Arthur Marcus Institute for Neurorehabilitation, Aging Research and Deanna and Sidney Wolk Center for Memory Health, Hebrew SeniorLife, a section of the journal Boston, MA, United States, 8 Department of Neurology and Harvard Medical School, Boston, MA, Frontiers in Neurology United States RECEIVED 09 May 2022 ACCEPTED 27 June 2022 PUBLISHED 19 July 2022 The problem: In the field of upper limb neurorehabilitation, the translation from CITATION research findings to clinical practice remains troublesome. Patients are not Boccuni L, Marinelli L, Trompetto C, receiving treatments based on the best available evidence. There are certainly Pascual-Leone A and Tormos multiple reasons to account for this issue, including the power of habit over Muñoz JM (2022) Time to reconcile research findings and clinical practice innovation, subjective beliefs over objective results. We need to take a step on upper limb neurorehabilitation. forward, by looking at most important results from randomized controlled Front. Neurol. 13:939748. doi: 10.3389/fneur.2022.939748 trials, and then identify key active ingredients that determined the success of interventions. On the other hand, we need to recognize those specific COPYRIGHT © 2022 Boccuni, Marinelli, Trompetto, categories of patients having the greatest benefit from each intervention, and Pascual-Leone and Tormos Muñoz. why. The aim is to reach the ability to design a neurorehabilitation program This is an open-access article distributed under the terms of the based on motor learning principles with established clinical efficacy and Creative Commons Attribution License tailored for specific patient’s needs. (CC BY). The use, distribution or reproduction in other forums is Proposed solutions: The objective of the present manuscript is to permitted, provided the original facilitate the translation of research findings to clinical practice. Starting author(s) and the copyright owner(s) from a literature review of selected neurorehabilitation approaches, for are credited and that the original publication in this journal is cited, in each intervention the following elements were highlighted: definition of accordance with accepted academic active ingredients; identification of underlying motor learning principles and practice. No use, distribution or reproduction is permitted which does neural mechanisms of recovery; inferences from research findings; and not comply with these terms. recommendations for clinical practice. Furthermore, we included a dedicated chapter on the importance of a comprehensive assessment (objective impairments and patient’s perspective) to design personalized and effective neurorehabilitation interventions. Conclusions: It’s time to reconcile research findings with clinical practice. Evidence from literature is consistently showing that neurological patients improve upper limb function, when core strategies based on motor learning principles are applied. To this end, practical take-home messages in the concluding section are provided, focusing on the importance of graded task practice, high number of repetitions, interventions tailored to patient’s goals and expectations, solutions to increase and distribute therapy beyond the formal patient-therapist session, and how to integrate different interventions Frontiers in Neurology 01 frontiersin.org Boccuni et al. 10.3389/fneur.2022.939748 to maximize upper limb motor outcomes. We hope that this manuscript will serve as starting point to fill the gap between theory and practice in upper limb neurorehabilitation, and as a practical tool to leverage the positive impact of clinicians on patients’ recovery. KEYWORDS stroke, neurorehabilitation, upper limb, motor learning, personalized medicine Introduction To make an example with a reaching task, performance will show higher improvements for frequently reached targets There is a translational gap between research findings and with stable conditions, in comparison to rarely reached clinical practice in the field of upper limb neurorehabilitation. target (use-dependent learning), or when there is excessive The latest decades have seen an exponential growth of evidence, variability of conditions (reinforcement learning). The person that has not been followed by an adequate evolution of being trained is aware of the goals of the training based on treatments offered to patients. One example is Constraint- instructions received (explicit strategies), but unaware of the Induced Movement Therapy (CIMT), an intensive, motor- kinematics and automatic adjustments underlying movement learning based intervention that has demonstrated the highest performance (implicit recalibration). A broader classification evidence level for the improvement of upper limb motor of motor learning principles related to neurorehabilitation function (1), with results successfully replicated in several have been proposed by Maier et al. in 2019, specifically by randomized controlled trials (2). Despite two decades of pointing out the following 15 principles: Repetitive practice, consistent findings, CIMT is rarely applied in most clinical spaced practice, dosage, task-specific practice, goal-oriented centers, whereas other interventions like Neurodevelopmental practice, variable practice, increasing difficulty, multisensory Treatment (NDT, also known as Bobath concept) are popular stimulation, rhythmic cueing, explicit feedback/knowledge of among therapists, irrespective that research evidence has shown results, implicit feedback/knowledge of performance, modulate equal or even inferior effectiveness for NDT, in comparison effector selection, action observation/embodied practice, motor with other approaches (1, 3, 4). There are likely multiple imagery, and social interaction (15). Given their practical reasons to account for this. Sometimes adoption of a certain utility to describe neurorehabilitation interventions, we will intervention in the clinical practice flow is challenging because refer to these principles throughout the manuscript. Regarding of time, resources, training, and other requirements. Other neuroplastic mechanisms, we should at least distinguish two times, the scientific evidence is difficult to apply to the individual models of brain reorganization after stroke, the interhemispheric patient since studies often focus on group average effects inhibition model and vicariation model, the former taking effectively disregarding – rather than leveraging – individual place after small lesions causing mild to moderate motor variability. The kind of personalized, optimal effective treatment impairment, the latter observed after larger lesions causing we all desire and that our patients deserve requires overcoming moderate to severe motor impairment (16). The key difference these challenges. is the competitive vs. cooperative role of the contralesional A first step toward evidence-based practice is the hemisphere. As a consequence, depending on the severity identification, within each intervention, of those core of motor impairment, therapeutic approaches may prefer to elements (active ingredients) that are essential for treatment target more uni- or bihemispheric activation, such as when effectiveness (5). For motor training approaches, active performing unilateral vs. bilateral arm training (17, 18). To ingredients could be for instance relative to the organization date, we are far from having assimilated the knowledge of of task practice (number of repetitions, variability, global active ingredients and motor learning principles within each vs. selective movement practice), the provision of a certain intervention. Coming back to the initial example, for most type of feedback (implicit vs. explicit feedback), and so on. therapists and clinicians CIMT is somehow synonymous of The following step is the identification of motor learning “the glove”; this is because, in the original CIMT trial, patients principles and neuroplastic mechanisms underlying recovery, had to wear a mitt on the unaffected hand to limit its use to interpret the theoretical basis and the concrete results during the day, and to remind patients to accomplish functional of any neurorehabilitation approach. We could start by tasks with the affected hand (19). This vision is reductionist considering four general motor learning principles: use- and misleading, considering that the original authors have dependent learning (6–8), reinforcement learning (9, 10), shown that wearing a mitt is ineffective when tested as isolated explicit strategies (11, 12), and implicit recalibration (13, 14). ingredient (20); in contrast, other key components of CIMT Frontiers in Neurology 02 frontiersin.org Boccuni et al. 10.3389/fneur.2022.939748 have shown consistent effectiveness, but unfortunately are still techniques for mobilization and tone reduction, the inclusion largely neglected. of bilateral arm training to accomplish tasks, and the use Therefore, the first objective of the present review was of assistive devices such as orthotics and functional electrical to define each intervention based on key active ingredients, stimulation (25). underlying motor learning principles and neural mechanisms likely taking place; the second objective was to draw inferences from research findings, to support our recommendations for Rationale clinical practice, familiarize clinicians with the methodology CIMT is a composite motor training approach, where of interpreting evidence, and stimulate further reading and we could identify the systematic application of the following critical appraisal of scientific literature (21). To this end, eight motor learning principles: repetitive practice, dosage, each chapter is organized with the headers “Intervention,” task-specific practice, goal-oriented practice, variable practice, “Rationale,” “Inferences” and “Recommendations” (see also increasing difficulty, explicit feedback/knowledge of results, and Table 1). Furthermore, a dedicated chapter on comprehensive modulate effector selection. The neural basis of the original assessment of neurological patients is provided, as cornerstone CIMT is the interhemispheric competition model, applicable requirement to design a personalized and effective upper limb for healthy individuals and patients with relatively small lesions neurorehabilitation treatment. Finally, we conclude with take- causing mild to moderate impairment (16). According to home messages and remarks with direct implications for both this model, unimanual activity is the result of the activation clinical practice and research. of the contralateral hemisphere that sends efferent input to the spinal cord, while at the same time inhibiting the other hemisphere through transcallosal pathways (28). Consequently, Motor training approaches: the tendency of using only the unaffected arm to accomplish Constraint-induced movement tasks may lead to activation of the unaffected hemisphere and therapy, bobath concept over-inhibition of the affected hemisphere, with negative impact on motor recovery (learned non-use). Therefore, CIMT was Constraint-induced movement therapy designed to restrain the use of the unaffected arm and promote unimanual training of the affected arm. On the other hand, Intervention when expanding CIMT to be applicable for severely impaired CIMT is the most widely investigated motor training patients, the vicariation model may be more suitable (16, 29). approach for upper limb neurorehabilitation, and one of the To summarize, in case of large lesions causing substantial most effective interventions to date (1, 2, 23). Being originally disruption of the corticospinal tract, the brain compensates developed for intensive rehabilitation of patients with mild to the lack of resources from primary sensorimotor cortex by moderate motor impairment (19) [bare minimum: 10◦ wrist recruiting alternative ipsilesional and contralesional pathways extension, 10◦ thumb abduction, and 10◦ extension any two to perform unimanual activities. In fact, there are several other digits (24)], CIMT has been investigated in a number of descending pathways that could subserve motor recovery, subsequent trials, although with different doses of therapy (2), arising from parietofrontal regions of both hemispheres and and recently adapted to be applicable also for those patients with forming direct and indirect (with the interpolation of reticular moderate to severe motor impairment (25). According to the formation) connections with primary motorneurons of the original authors, CIMT is a composite intervention that includes affected arm (30, 31). Given the cooperative role of the three main elements: restrain of the unaffected hand for the contralesional hemisphere, and the objective difficulty on 90% of waking hours, task-oriented training for up to 6 h/day, achieving a functional task with the sole use of the affected and a transfer package to foster adherence to the intervention arm, the expanded CIMT protocol considered the inclusion of and behavioral changes in the long term (use of logbook, diary, bilateral arm training, less restrictions of the unaffected arm, and home practice) (5). Within task-oriented training we can further systematic adoption of assistive devices (25). distinguish two components, i.e., task practice and shaping. Task practice is the training of an activity of daily living for about 15–20 min, like preparing a meal, while shaping is the repetitive Inferences performance of components of functional tasks, such as reaching To understand the relative importance of each component and grasping movements (26). A narrative review of Page et al. on the final motor outcome, it’s useful to compare the illustrates practical challenges and opportunities of CIMT, and effectiveness of CIMT vs. conventional therapy, and the provides explicit examples to facilitate the implementation of effectiveness of the original CIMT trial vs. modified CIMT CIMT in a clinical setting (27). Notably, in the adaptation of versions, generally characterized by reduced time of affected- CIMT for severely impaired patients (“expanded CIMT”), three arm therapy and unaffected-arm restrain, as compared to the important ingredients have been the adoption of preparatory original version. Despite the heterogeneity of study designs, Frontiers in Neurology 03 frontiersin.org Boccuni et al. 10.3389/fneur.2022.939748 TABLE 1 Summary of upper limb neurorehabilitation interventions according to key active ingredients, rationale and recommendations for clinical practice. Key active Key motor Recommendations Interventions ingredients learning principles and neural mechanisms Motor training approaches CIMT Shaping Explicit learning Indicated for mild to Task practice Repetitive practice moderately impaired Goal-oriented practice patients; consider Task-specific practice strategies for Interhemispheric independent and inhibition model distributed practice; use of a mitt is not mandatory Expanded CIMT Shaping Explicit learning Indicated for severely (adaptated for severely Task practice Repetitive practice impaired patients; impaired patients) Inclusion of orthotics, Goal-oriented practice consider devices to assist McCabe et al. (22) FES and bilateral Task specific practice movement execution; (intensive rehabilitation training to Vicaration model include both unilateral for severely impaired accomplish tasks and bilateral arm patients) training Bobath Concept Movement quality Explicit learning Suitable for any level of Afferent input to (implicit feedback/ disability, but currently improve motor control, knowledge of equally or less effective body schema and performance) than other approaches. motor learning Implicit learning Consider repetitive Facilitation techniques (sensorimotor practice (high number of (handling, integration) repetitions) to increase environmental Task specific practice the effectiveness of the adaptation, intervention. verbal cueing) Interventions assisting movement execution Robotic therapy Repetitive movement Explicit learning Particularly useful to performance Repetitive practice assist shoulder and elbow movements (reaching) Functional electrical Repetitive movement Explicit learning Particularly useful to stimulation performance Repetitive practice assist finger movements Sensorimotor integration (grasping) splint/orthotics Repetitive movement Explicit learning Particularly useful for performance Repetitive practice wrist and thumb functional positioning Interventions providing feedback and multisensory stimulation Virtual reality Motivation, engagement Explicit learning Particularly useful to Visual and Explicit feedback increase motivation, auditory stimuli Multisensory stimulation avoid boredom and promote independent practice. Consider the provision of cues about movement quality (implicit feedback) (Continued) Frontiers in Neurology 04 frontiersin.org Boccuni et al. 10.3389/fneur.2022.939748 TABLE 1 Continued Key active Key motor Recommendations Interventions ingredients learning principles and neural mechanisms Action observation Immediately after action Explicit learning Indicated for severely observation, patients Action observation impaired patients. Useful have to perform the Mirror neuron network as additional therapy same movements with time in preparation for the affected limb motor training Mirror therapy Large mirror Explicit learning Indicated for severely Unilateral arm Action observation impaired patients. Useful performance as additional therapy (unaffected side) time No object manipulation Motor imagery PRACTICE principles Explicit learning Indicated for severely Mental practice impaired patients. Useful as additional therapy time in preparation for motor training Non-motor interventions priming neuroplasticity Non-invasive brain Stimulation parameters Modulate neural activity Consider different stimulation and localization of Prime motor learning protocols depending on targets acquisition the level of impairment Interhemispheric and underlying inhibition model neural mechanisms. Vicariation model Consider performing motor training during (tDCS) or after (TMS) neuromodulation Somatosensory electrical More than one motor Increased activation of Train patients to use the stimulation point at the same time, sensorimotor areas stimulator high frequency and Prime motor learning independently, ideally in intensity near motor acquisition the 2 h preceding threshold therapy. Consider providing stimulation concomitant with therapy Aerobic training Exercise intensity Prime motor learning Consider short high Performance consolidation intensity interval immediately after motor training protocols training session immediately after the motor training session patients receiving CIMT consistently showed better outcomes restraint of the unaffected arm and shaping techniques were in terms of arm-hand activities and self-reported amount the two factors applied by any CIMT intervention, but not and quality of arm-hand use, than conventional therapy (2). included in the conventional therapy approaches. Therefore, However, there were no significant differences in effect sizes we can already focus our attention specifically on these between original and modified CIMT versions (2). Notably, two elements. Frontiers in Neurology 05 frontiersin.org Boccuni et al. 10.3389/fneur.2022.939748 Restrain of the unaffected arm has been investigated as an value, to keep the patient motivated to challenge him-herself isolated intervention, namely “forced use therapy,” but failed on subsequent trials (5, 26). Complex functional tasks (for to produce any additional benefit on top of conventional instance, drinking water from a bottle) are initially broken therapy, for self-perceived amount and quality of arm-hand down into simpler motor components (arm reaching, hand use (2). The same authors of the original CIMT compared grasping, elbow flexion/extension, etc), until the level that can be groups of chronic stroke patients receiving comparable doses practiced effectively and repeatedly by the patient; as the patient of motor therapy (shaping), but different levels of arm-hand progresses, components are gradually practiced in combination, restrain, and found no between-group differences in motor until the whole functional task can be accomplished. The outcome (20). According to Taub et al., “there is nothing level of difficulty is also adjusted by modulating the required talismanic about use of a sling, a protective safety mitt, or number of repetitions, speed, and accuracy. The selection of other constraining device on the less-affected [upper limb]” the task to be trained is based upon three criteria: (a) being (32). The point is not wearing a physical restraint, but focused on the specific motor impairment shown by the patient rather finding a way to counteract the tendency of using (which joints/muscles are involved? which movements are exclusively the less-affected arm for all daily activities, which compromised?); (b) being judged by therapists as having the inevitably leads to learned non-use; in this perspective, shaping potential to improve the motor outcome of the patient (is is in itself already a form of restraint (33). Besides CIMT, there a potential for recovery?); (c) being the task chosen by a recent meta-analysis (21 studies, 842 subjects) indicated the patient among a set of similar tasks, in order to meet higher improvements for motor impairment, and a trend patient preferences and involve him/her in the decision making toward higher functional outcomes, for bilateral arm training process of selecting a task (26). In recent years, high-intensity as compared to unilateral arm training (34). Such findings upper limb rehabilitation trials have consistently reported challenge the clinical relevance of unilateral training of the clinically meaningful motor improvements by applying shaping affected arm by restraining the unaffected arm, especially if principles, such as decomposition of functional activities in we consider that most activities of daily living require bilateral simpler motor tasks, systematic performance of repetitions and arm use, and that restraining the use of the unaffected arm provision of feedback, tasks being specific to motor impairments is impractical for more severely affected patients. In fact, and toward patient’s preferences and goals, and progressive the expanded CIMT protocol, adapted for those patients increase of task difficulty in order to meet patient’s capabilities with moderate to severe motor impairment, also considered and approximate, as much as possible, the functional activity to bimanual arm training as part of the intervention, and a be trained (22, 38, 39). reduced time wearing the mitt (25). Moreover, there is An important finding for CIMT and other high-intensity accumulating evidence that contralateral arm training, i.e., approaches, is the difference in outcomes depending on the training of the unaffected arm because of inability to elicit stage of recovery. Notably, high intensities of therapy seem more movements on the affected arm, could be beneficial on both consistently beneficial in the chronic phase (6, 8, 24), than in the functional and neural domain (35, 36). The mechanism the acute/sub-acute phase after stroke (27, 28). One possible of cross-education (improvement of motor function in the explanation of such conflicting results is that blocked schedules untrained arm following contralateral arm training) may explain of intensive training in the early phases post stroke may this counterintuitive phenomenon. In a recent consensus paper, generate unwanted overload, detrimental for motor recovery neurophysiologists and clinicians agreed on that a slight increase and learning (29). It has been suggested that distributing therapy in interhemispheric imbalance is acceptable, if function of in short sessions throughout the day (spaced practice) might the affected side is increased following training of the sound optimize motor learning (28, 30) and even the likelihood of a limb (37). favorable outcome (31) in the early phases after stroke. Shaping is perhaps the most interesting element of CIMT, surely as a key factor that determined the superiority of any CIMT intervention over conventional therapy, but also because Recommendations it could be easily implemented in any motor intervention. 1. CIMT is an effective upper limb neurorehabilitation Shaping can be defined as a structured motor skill training, approach that should be embraced by clinicians and typically organized in ten 30-s trials for each motor function adapted to optimally fit with specific patient’s needs and to be trained, with explicit feedback provided at the end resource constraints. of each trial (5, 26). Movements are organized as discrete 2. Currently, the design of high doses, spaced practice repetitions, so that it’s possible to train the same pattern of interventions in the acute phase represent a challenge for actions consistently and monitor progressions by measuring the healthcare providers, and a relatively unexplored, yet promising number of repetitions performed, the time taken, the distance field of research. Being practically unfeasible for therapists to covered and/or the level of spatial/temporal accuracy while be present with patients the whole day, soon wearable/portable attaining a specific goal. The best performance within each assistive devices will likely play a key role to achieve high doses, trial is recorded and presented to the patient as reference low intensity therapy regimens. Frontiers in Neurology 06 frontiersin.org Boccuni et al. 10.3389/fneur.2022.939748 Bobath concept the publication of core characteristics of the Bobath Concept (40), and the development of intensive rehabilitation programs Intervention based on the Bobath Concept, that led to positive and clinically Bobath Concept, or Neurodevelopmental Treatment meaningful improvements of upper limb motor impairment in (NDT), is one of the most popular treatment approaches in the subacute phase after stroke (44). neurorehabilitation (4). NDT has been defined as a conceptual framework with the following paramount characteristics: first, the attention upon quality of movement; second, the influence Recommendations of afferent input on motor control, body schema and motor We believe that a clearer definition of the intervention learning; and finally, the use of facilitation techniques, which protocol, an update of NDT fundamentals based on scientific includes therapeutic handling, environmental adaptations and evidence, and a broader consideration of motor learning verbal cueing (40). principles, with higher emphasis on the volume and intensity of the treatment, might help improve the reproducibility and efficacy of NDT. Rationale There are two motor learning principles that are systematically applied within NDT. The first one is task- Interventions assisting movement specific practice: by practicing functional tasks patients focus execution: Robotics, functional on learning how to overcome specific limitations in activities electrical stimulation, and orthotics of daily living. The second one is the provision of implicit feedback, which could be defined as attention upon movement Interventions quality (15). Indeed, a considerable portion of the treatment is dedicated to the improvement of movement quality, by making Robotics assist movement execution by providing anti- patients aware of correct movement patterns vs. compensatory gravity support and/or by exerting external forces to move and maladaptive movements. A third element is represented joints in a specific direction. Functional electrical stimulation by the neural basis underlying “the influence of afferent input” generates movement by triggering internal forces (muscle “therapeutic handling,” and “environmental adaptations.” One contraction), with the application of electricity flowing in hypothesis is a multilevel sensorimotor integration (spinal, between pairs of electrodes placed over the muscle belly, subcortical, cortical) that is necessary for the initial phases at intensities above the motor threshold. For both robotics of motor learning acquisition at both conscious (cortical, and functional electrical stimulation, it’s preferable that the explicit strategy) and unconscious (spinal, subcortical, implicit patient is actively engaged as much as possible in movement recalibration) levels. performance, with assistive devices set to provide the least amount of assistance to accomplish a certain task. If the patient is unable to perform any movement, they may be Inferences used to provide passive mobilization and preserve mobility, Several systematic reviews, comparing NDT vs. other to maintain/improve muscle trophism (for functional electrical treatment approaches, have provided substantial evidence that stimulation), and to normalize muscle tone (45–47). Orthotics NDT have comparable or even unfavorable effects on several provide joint stability in a functional position, which in turn upper limb motor outcomes (1, 3, 4). One reason could may allow better movement execution and/or increased volume be that focusing excessively on activities of daily living and of repetitions for adjacent structures, or at least prevent soft movement quality might come at the expenses of the number tissue changes secondary to prolonged immobility in vicious of repetitions performed, which negatively impact core motor postures (contractures, muscle stiffness, joint deformities etc.). learning principles like repetitive practice and dosage. Another Active ingredients are the following: for robotics, we should point of criticism is that NDT historically advised clinicians distinguish between end-effectors vs. exoskeletons, the former against engaging patients in resistance training because it leaving more freedom of movement and thus more suitable may increase muscle tone (41), despite evidence showing that for mild to moderate impairments, the latter taking control resistance training improves strength and could be beneficial over multi-joint coordination, which is helpful for moderate for motor function, without any increase in spasticity (41–43). to severely impaired patients. Other elements to consider is Finally, there is scant literature documenting the content and whether the robot allows 2D vs. 3D movements, to which theoretical foundations of the Bobath Concept, which is typically extent it is possible to train proximal and distal components taught orally in dedicated courses, thus making NDT prone to at the same time, or to interact with physical objects. For detrimental heterogeneity in the interpretation and application FES, active ingredients are stimulation parameters, in particular of the techniques (4). Recently, promising advancements were the possibility of eliciting sustained muscle contraction reliably Frontiers in Neurology 07 frontiersin.org Boccuni et al. 10.3389/fneur.2022.939748 without causing discomfort and pain (48). Furthermore, the robotics, vs. functional electrical stimulation (FES) (22). Despite possibility of triggering muscle contraction may be preferrable being applied on severely impaired patients in the chronic to cyclic stimulation, because of the coupling between electrical phase after stroke, clinically meaningful improvements in motor stimulation, movement execution and intention to move (49). impairment were detected for all intervention groups, without For orthotics, the possibility to adapt and personalize the any statistical between-group difference. Another large (n = device is fundamental to ensure functionality and patient’s 127) although less extensive (36 h in 12 weeks) multicentre adherence. Ideal solutions are functional hand splinting made rehabilitation trial did not find any clinically meaningful of thermoplastic material, by molding the orthosis directly on difference between stroke patients receiving equal amounts of patient’s hand. intensive robotic and therapist-patient therapy (51). Systematic meta-analysis on the effectiveness of robotic therapy (which included the two aforementioned studies) confirmed that there Rationale was no clinically meaningful improvement of motor outcomes, as compared to equal amounts of other interventions (52). A common goal of assistive devices is the improvement Similarly, a systematic review indicated that FES therapy was of functionality, either active functionality (better movement not superior to other training modalities for the improvements quality, higher number of repetitions) and passive functionality of upper limb motor function (53). Therefore, if the patient (prevention of secondary complications from non-use and performs 100 repetitions of reaching to grasping movements, immobility). In case of active functionality, the underlying motor improvements should be rather similar, no matter motor learning principle is repetitive task practice enhanced whether the patient received the assistance from a therapist, by the adoption of assistive devices. Other motor learning a robot, a FES equipment, a combination of these three principles may be present, depending on the overall content types of interventions. Notably, most effective interventions of the motor training program, the guidance of the therapist considered a composite program, where robotic and/or FES and the visual/auditory/tactile/proprioceptive feedback interventions were always performed with various degrees directly associated with the device. Finally, if devices are of personnel assistance, and integrated on top of therapist- wearable/portable, this could lead to the application of the patient sessions (22, 25, 38, 39, 44). Equal effectiveness principle of spaced practice/distributed practice throughout the between technological and human interventions should be day, and increased total dosage of therapy delivered. seen as confirmation that motor learning principles, like intensity of training and task specificity, work uniformly across different types of approaches. Therefore, the choice Inferences of an intervention over another should depend on factors such as cost-effectiveness, personnel availability, and the Patients with moderate to severe motor impairments opportunity to provide additional training to the patient require physical assistance to perform active-assisted motor in group sessions, independently from the therapist, or training of the affected limb. Being the distribution of motor even remotely. impairments rather evenly distributed at the whole upper limb, That said, we should specify that some interventions have usually patients require both proximal (trunk, scapula, shoulder, more practical applicability for proximal vs. distal upper limb elbow) and distal (wrist, hand, fingers) assistance at the same components (22). Assistive devices that showed positive effect time (50). on upper limb motor impairment were shoulder-elbow-wrist In the simplest form, the patient may use the unaffected robotics and wrist-hand-finger FES applications (1). Proximal arm to support the affected arm, or the therapist may use of robotics is in line with the fact that most exoskeletons set the scapula in the proper orientation, support the may support as needed the weight of the arm. In general, weight of the arm and orient the wrist and the hand all antigravity support systems allow patients to perform a in order to perform functional activities, such as reaching wider range of movements, higher number of repetitions, and grasping (40, 44). Technological devices may be used and better movement quality, especially when supervised by as complementary interventions to perform active-assisted a therapist and/or equipped with sensors for feedback on arm-hand training, with the therapist having more freedom movement performance. A predominantly distal use of FES, to provide verbal/physical guidance for correct movement on the other hand, is the result of the fact that electrical execution, or even without the constant presence of the stimulation is more capable of generating effective movements therapist, to perform additional therapy on top of therapist- at the level of wrist and finger into flexion/extension, and to patient sessions. some extent also elbow flexion/extension, than of producing The most extensive upper limb rehabilitation trial provided shoulder/trunk movements. The main two variables to consider 300 h of therapy in 5 weeks (5 h/day), and compared the here are the minimum number of muscles necessary to effectiveness of therapist-patient motor learning training, vs. produce the required movement, and the amount of force Frontiers in Neurology 08 frontiersin.org Boccuni et al. 10.3389/fneur.2022.939748 that needs to be generated. Elbow/wrist/hand movements into equipment, such as a helmet with a screen inside or gloves flexion/extension can be elicited by contracting one muscle at a fitted with sensors” (54). Active ingredients that likely play time, eventually providing enough stability to other districts; one a role are immersive vs. non-immersive VR experience (55); example is the application of electrical stimulation of extensor the therapeutic content of the exercise, i.e., being specifically digitorum communis for finger extension, in combination with designed for neurorehabilitation purposes (56); the type of stabilization of the wrist in neutral position (for instance, with feedback being provided (explicit and/or implicit feedback) and orthosis). The same cannot be applied so easily to the (57); and the integration of multisensory stimuli (visual, shoulder, because any movement requires the coordination auditory, haptic) (15). of a higher number of muscles at the same time, and the control of higher degrees of freedom; for instance, shoulder flexion involves the coordinated activation of the deltoid, Rationale rotator cuff muscles, trapezius, serratus anterior and enough Motor learning principles that fit well with VR are goal- core strength. oriented practice, explicit feedback/knowledge of performance, Finally, if robotics have predominantly a proximal and multisensory stimulation. Furthermore, because of patient’s application at the level of the shoulder and the elbow, engagement (by gamification of therapy) and provision of and FES is effective for finger movements generated by automatic feedback, VR could significantly improve dosage and forearm muscles, functional hand splinting at the level distribution of training. of the wrist and the hand may help stabilize the wrist at the desired angle, and recreate a functional shape of the hand as done by intrinsic hand muscles, with a Inferences smooth palmar concavity and thumb in opposition, while Feedback from a motor act refers to the knowledge leaving fingers free to move. All these assistive devices of the final result (explicit feedback) or to the knowledge are not mutually exclusive, but rather complementary and of performance/movement quality (implicit feedback) have been used simultaneously in composite upper limb (15). It’s worth noting that the terms explicit and implicit neurorehabilitation trials (25, 39) to perform whole arm also refer to learning mechanisms, with explicit learning functional movements, such as combined reaching and being aware/intentional and implicit learning being grasping tasks. unaware/unintentional (58); therefore, the terms differ substantially depending on the argument. Explicit and implicit feedback both subtends explicit learning, with the focus Recommendations purposely directed toward the end results of a movement (target reached), or how well the movement was performed Therapists should consider implementing several (coordination, fluency, lack of compensatory movements). assistive devices for the rehabilitation of moderate to A practical example is a patient training forward reaching: severe upper limb paresis, within their own treatment explicit feedback consists of the successful grasp of a physical plan, to help patients perform functional movements, object (a bottle on the table) and positive encouragements from but also to give “extra hands” to the therapist and the therapist for task completion; implicit feedback consists leave more space for movement guidance, motivation, on verbal and physical guidance to perform the movement and coaching. without excessive trunk flexion or shoulder elevation. Feedback is an integral part of learning and has been developed in different forms in any motor training program. There are Interventions providing feedback interventions that have been specifically designed to modulate and multisensory stimulation: Virtual feedback, such as VR, action observation, mirror therapy and reality, action observation, mirror motor imagery. therapy and motor imagery One modality is to provide enhanced knowledge of result and/or performance during motor skill training, Virtual reality so that the patient can better learn from errors; this strategy is used in VR, for those patients capable of Intervention performing a functional task (independently or with the Virtual reality (VR) has been defined as “the computer- use of assistive devices). Furthermore, an enriched and generated simulation of a three-dimensional image or immersive VR experience, with the provision of different environment that can be interacted with in a seemingly sources of stimuli (visual, auditory haptic) can improve real or physical way by a person using special electronic patient’s engagement and motivation, which in turn has Frontiers in Neurology 09 frontiersin.org Boccuni et al. 10.3389/fneur.2022.939748 positive effects on performing higher amounts of therapy, at being played, and guide patient in the subsequent task oriented sustained attention. training, for a total of 30–40 min of therapy per day (61, 62). A systematic Cochrane review comparing VR vs. Mirror therapy consists of placing a mirror vertically at conventional therapy found no statistically significant the patient’s midline, so that the unaffected side is reflected, differences on upper limb motor function (59). However, thus creating a visual illusion that the image in the mirror when VR was provided as additional therapy on top of corresponds to the affected side. Average training intensity conventional therapy, results were significantly better than consists of 30 min per day, 5 days a week, for 4 weeks, typically conventional therapy in isolation (59). A recent three-arm provided as additional therapy to motor training (63). There randomized controlled trial compared high-dose VR, vs. is a tendency toward better results when using a large mirror, high-dose conventional therapy, vs. conventional therapy; for performing unilateral movements with the unaffected arm, upper limb motor function, comparable results were found without object manipulation (64). between high-dose VR vs. high-dose conventional therapy, and Motor imagery is the mental rehearsal of physical higher gains in favor of both high-dose groups, as compared to movements (65). Mental practice is structured as a 30-min conventional therapy (38). Therefore, one clear advantage of VR session, where the patient listens to an audio file in a dedicated, is the opportunity to increase the volume of therapy, while at the quiet room; the audio file comprises 5 min of progressive same time enhancing patient’s engagement and sensorimotor relaxation at the beginning and at the end of the session, and integration (60). 20 min of guided motor imagery (65). Principles of mental practice are part-whole practice with progressive difficulty, repetitive and goal-focused practice, client- and impairment- centered, and with emphasis on task accomplishment (66). Recommendations Movement quality is a cornerstone ingredient of many interventions, by helping patients discriminate between correct and incorrect movements, thus preventing maladaptive Rationale An alternative approach to VR is to provide patients learning. Intrinsic feedback gives information about movement with a completely fictitious experience of a functional quality, and seems to be superior to extrinsic feedback for movement, regardless of the actual movement performed/not long-lasting recovery of normal motor patterns (57); notably, performed, thus reducing feedback of their own body state. to decrease the risk of over-reliance on feedback, a faded The fictitious experience can be externally (action observation, schedule should be considered (57). Unfortunately, most VR mirror therapy) or internally (motor imagery) generated; devices provide a great amount of extrinsic feedback, with the goal is to activate the mirror neuron system, which has intrinsic feedback totally absent or visually presented in the overlapping pattern of activation during action execution, form of mini-avatar in the corner of the screen. In this form, action observation and motor imagery, thus represents a the provision of intrinsic feedback depends upon constant potential way to trigger motor learning and neuroplasticity guidance by the therapist; however, if we agree that the greatest without even producing a motor action (67); which is advantage of VR is to provide therapist-free additional therapy particularly appealing for those patients with moderate time, developers of new VR applications should focus on to severe motor impairment (68). Besides motor learning solutions to train the patient independently, with automatic mechanisms specifically pertaining to these interventions provision of adequate intrinsic feedback, preferably delivered as (action observation/embodied practice, motor imagery) another auditory/haptic feedback, rather than visual (15). As a technical motor learning principle to consider is dosage, because of the note, wearable VR glasses, integrated with positional sensors possibility to train unassisted/unsupervised, thus increasing the of different body segments, might be an ideal starting point in overall volume of therapy performed. this direction. Inferences Action observation, mirror therapy and Several systematic reviews have been already published, motor imagery overall confirming the effectiveness of these interventions. In particular, a Cochrane review concluded that action observation Interventions determines a statistically significant, albeit not clinically Action observation typically consists of watching few meaningful, improvement in upper limb motor function and minutes of video tapes about upper limb functional tasks, dependence on activities of daily living, the largest effect being performed by healthy subjects; the patient is aware that he/she reported for hand function (69). Another Cochrane review will practice the same task immediately afterwards, and therapist found overall moderate-quality evidence that mirror therapy is constantly present to ensure patient’s attention to the video has a positive effect on both upper limb motor function, motor Frontiers in Neurology 10 frontiersin.org Boccuni et al. 10.3389/fneur.2022.939748 impairment and activities of daily living, though effect size varies upper limb neurorehabilitation, the goal is to prime depending on the control condition (63). Finally, systematic motor learning acquisition, typically with excitation of reviews indicated effectiveness of motor imagery on improving the affected sensorimotor cortex and/or inhibition of upper limb motor function (1, 23, 70). competitive brain areas before (TMS) or during (TCS) motor training. Recommendations Action observation, mirror therapy and motor imagery Inferences are effective interventions requiring minimal resources, Despite the great potential to enhance the that could be considered as additional therapy to prime effectiveness of neurorehabilitation interventions, there motor learning acquisition before the formal patient- is a wide variability in response to non-invasive brain therapist session of motor skill training, while virtual stimulation (75). Here we reported four major sources of reality could be used to increase the amount of active variability, and provide suggestions on how to account motor training of the affected arm, possibly administered for them: independently from the therapist and in a stimulating, 1) Severity of motor impairment. Patients with different playful way. levels of motor impairments have quantitative, but also qualitative differences in terms of underlying neural Non-motor interventions priming correlates. Quantitatively, the larger the lesion size at the level of the corticospinal tract, the more severe the motor neuroplasticity: Non-invasive brain impairment (76, 77). To recap, there are two distinct stimulation, somatosensory models of neuroplastic changes following brain lesions: the electrical stimulation, aerobic interhemispheric competition model, where the activation training of the unaffected hemisphere over-inhibit the activity of the affected hemisphere, and the vicariation model, where Non-invasive brain stimulation (NIBS), somatosensory the activation of the unaffected hemisphere is beneficial to electrical stimulation and aerobic training are examples of partially compensate for the loss of function at the level of promising interventions targeting biochemical, synaptic the unaffected hemisphere (16, 78). The interhemispheric and neuroplastic mechanisms underlying motor learning, competition model is valid for patients with relatively small although they do not consist of any formal motor lesions resulting in mild to moderate motor impairments, skill practice, neither active nor imaginative. They are while the vicariation model is applicable for patients generally provided closely to a motor training session, with larger lesions and more severe motor impairments. to enhance motor learning acquisition (immediately As a consequence, it is necessary to apply different before or during practice) and consolidation (immediately neuromodulation strategies, depending on the level of motor after practice). impairment (16, 79). 2) The interplay between neuromodulation and motor activity. Motor activity performed either immediately before, during Non-invasive brain stimulation or after neuromodulation can potentiate its effectiveness, but also have undesired consequences, such as the abolishment Intervention or even the reversal of the neuroplastic effects we were Non-invasive brain stimulation (NIBS) refers to initially aiming at (75). Therefore, enough rest time (a interventions to modulate neural excitability via transcranial few minutes) should be allocated before and after the stimulation (71). There are two main NIBS modalities, stimulation protocol. Transcranial Magnetic Stimulation (TMS) and Transcranial 3) Stimulation parameters. Slight modification of stimulation Current Stimulation (TCS). Active ingredients are the following: parameters can have relevant and somehow counterintuitive stimulation target, stimulation parameters (intensity, frequency, consequences. For instance, increasing the duration of stimulation protocol), duration, concurrent motor training. the stimulation protocol reverses the effect of intermittent International guidelines have been published as reference for theta burst stimulation from facilitatory to inhibitory, while researchers and clinicians (72, 73). continuous theta burst stimulation switches from inhibitory to facilitatory (80, 81). Moreover, increasing stimulation intensity (82) or frequency (83) does not necessarily lead Rationale to enhanced effectiveness. Therefore, stimulation parameters NIBS aims at modulating cortical excitability, either by should be carefully selected based on evidence of efficacy and inhibiting or facilitating neural discharge (74). Regarding within safety recommendations (72). Frontiers in Neurology 11 frontiersin.org Boccuni et al. 10.3389/fneur.2022.939748 4) Aftereffect duration. Long-lasting effects upon cessation activation of sensorimotor areas before or during motor of the stimulation could have important therapeutic training (100). consequences, as intensive motor training could be performed in a context of optimal neural state. However, many stimulation protocols have short-lasting effects (< Inferences 30–60 min); as mentioned previously, concomitant motor From a theoretical standpoint, it’s important to clarify practice or extending the duration of the stimulation that electrical stimulation should be considered as a pure are unreliable strategies. One emerging solution is the somatosensory intervention only when the stimulation performance of several stimulation trains within the is above the sensory threshold, but below the motor same day (spaced stimulation) (75, 84). For instance, threshold. In contrast, functional electrical stimulation is the application of two trains of continuous theta burst a motor intervention, as it requires intensities well above stimulation, with a rest period of 10–15 min in between, the motor threshold to assist the execution of arm-hand has shown long-lasting effects of at least 2 (and up to 10) h movements. It is unclear whether electrical stimulation at (85, 86); four trains of continuous theta burst stimulation or above the motor threshold, resulting in a visible muscle (at zero, 15, 60 and 75 min) up to 32 h (87); and finally, twitch but no overt movement, should be classified as eight trains in 2 days produced a clinically meaningful somatosensory or motor interventions. However, from a improvement of at least 3 weeks (88). Notably, the outcomes clinical perspective, the use of electrical stimulation near of the studies were the amplitude of motor evoked potentials, the motor threshold level could represent an appealing saccadic eye latency and visuospatial neglect. Future solution to prime neuroplasticity (101), while not having a studies should investigate similar paradigms for motor practical interference with other motor training interventions rehabilitation interventions. performed at the same time, such as motor skill training and motor imagery (102). Indeed, peripheral electrical stimulation induces increased excitability of the corticospinal Recommendations tract (101), especially when delivered synchronously at Regarding upper limb neurorehabilitation, there is currently more than one motor point (103), at high frequency contrasting evidence on the effectiveness of non-invasive brain (≥30 Hz) and at intensities above the motor threshold, stimulation, with some reviews in favor (89, 90) and others sufficient to produce visible muscle twitch or contraction against (91, 92) its added value on top of conventional (104). Notably, in healthy individuals the application of therapy. Further advances in the field might arise by controlling electrical stimulation concomitant to motor skill training for factors causing variability in treatment response, and resulted into higher motor learning indexes, as compared by exploring approaches capable of long-lasting and reliable to consecutive sessions of electrical stimulation and motor neuroplastic changes. training (105). Somatosensory electrical stimulation Recommendations There are still several unexplored yet promising Intervention applications of electrical stimulation, namely using near- The effect of somatosensory electrical stimulation on upper motor threshold intensities, at more than one motor point, limb motor function after stroke has been investigated in a and concomitant to other training regimens, that could number of randomized controlled trials (93–98). Typically, increase the overall effectiveness of therapy on motor learning electrical stimulation was administered for 120 min, before the and recovery. motor intervention, with low frequencies (10 Hz) and intensity above the sensory threshold, but below the motor threshold (99). Only one systematic review (5 studies, 95 subjects) Aerobic training investigated specifically somatosensory electrical stimulation on upper limb motor performance after stroke, demonstrating Intervention statistically significant better motor performance in favor of The American College of Sports Medicine (ACSM) defines repeated peripheral sensory stimulation (99). aerobic exercise as any activity recruiting large muscle groups, maintained continuously and rhythmic in nature (106). Active ingredients could be defined according to the Rationale following variables: training modality (cyclic movements vs. The objective of somatosensory electrical stimulation discrete repetitions), training intensity, duration, inter-session is to prime motor learning acquisition, by increasing the intervals and overall intensity and volume of the program, Frontiers in Neurology 12 frontiersin.org Boccuni et al. 10.3389/fneur.2022.939748 in terms of frequency of sessions per week and total number intensity, the higher and enduring the therapeutic gains of weeks. (111, 114). From comprehensive assessment to Rationale The main goal of aerobic training, when personalized interventions performed immediately after motor skill training, is to enhance motor learning consolidation (107– Personalized, patient-centered goal setting is perceived 109). important by stroke survivors and caregivers, but this practice is often lacking (115). Tailoring neurorehabilitation to individual needs and preferences, monitoring progressions, and maintaining a positive and proactive attitude toward Inferences realistic goals, is important to improve motivation, Motor memory encoding and consolidation are two adherence, effectiveness and patient’s satisfaction of the consecutive phases of the motor learning process. In healthy treatment received (116). The foundation of personalized individuals, aerobic exercise enhances motor memory interventions is a comprehensive assessment of both objective consolidation, but not acquisition, with strongest effects impairment and patient’s perspective, and the definition shown for high intensity exercises (107). Aerobic training of shared goals and expectations between the patient and performed immediately after motor skill training improves the therapist. sleep-dependent consolidation (107), and leads to higher effects Figure 1A illustrates a schematic of the proposed workflow. on long-term retention than when performed immediately The first step is to determine objective deficits, for instance before motor skill training, or when aerobic training is by using validated clinical assessments covering the ICF not performed (108). In line with these findings, patients domains of body function and structure (impairments) and in the chronic phase after stroke showed better retention activity (limitations) (117). The second step is to consider when 15 min of high intensity interval training (HIIT) patient’s perspective to quantify real-life perceived functionality was performed immediately after motor skill training, as (validated questionnaires) and to determine goals for treatment. compared when motor skill training was followed by a However, sometimes it’s difficult for patients to identify their period of rest (109). HIIT consists of repeated, short bouts own functional goals (27). To facilitate the decision-making of exercise at elevated effort, interspersed by periods of process, it’s recommended to use semi-structured interviews low-intensity exercise or rest. In the rehabilitation field, such as for the Canadian Occupational Performance Measure the main attractiveness for HIIT is that results, even for (118), and SMART principles for patient-centered goal setting deconditioned patients, in cumulatively more time of exercise (119). Finally, there is growing interest in the development of at high intensity and lower perceived effort, compared to wearable sensors and remote assessments to automatically and moderate-intensity continuous aerobic training (110). A reliably monitor real-life functional use of the affected arm (120– recent review indicated the potentialities of HIIT, as safe and 122). One of the greatest advantages of tele-assessment is that effective intervention to promote cardiovascular, functional it may be diriment to interpret the potential gap between what and neuroplastic outcomes post stroke, but at the same is objectively measured in the clinic, and how patient perceives time highlighted that larger randomized trials are needed to arm functionality (123, 124). confirm findings from pilot studies (111). It’s important to Figure 1B provides a practical example of clinical highlight that there are no specific safety issues for HIIT, as assessments to determine objective upper limb deficits compared to moderate intensity continuous cardiovascular and select appropriate treatment strategies. The criteria for exercise (111). selecting each assessment measure where the following: (1) well-established psychometric properties (validity, reliability, sensitivity to change); (2) clinical utility, meaning the ability to Recommendations already direct therapists toward concrete therapeutic goals; (3) There is international consensus that, once the patient easiness of use, in terms of training and equipment required, is medically stable and cardiopulmonary exercise testing time to perform the assessment, and potential contraindications. has been performed to rule out risks of adverse events, For instance, the Stroke Upper Limb Capacity Scale (SULCS) is an aerobic training program should be implemented a clinical assessment of upper limb activity, with excellent inter- in the general rehabilitation program (112, 113); the rater reliability and high responsiveness to change (125–127); beneficial effects on cardiovascular status, functional there is minimum training and equipment required; tasks are recovery and motor learning are directly associated organized hierarchically, so that therapists may decide to start with the intensity of the exercise so that, the higher the from the beginning or from the end of the assessment, and to Frontiers in Neurology 13 frontiersin.org Boccuni et al. 10.3389/fneur.2022.939748 FIGURE 1 (A) Schematic representation of comprehensive upper limb neurorehabilitation assessment; (B) example of assessment algorithm for objective upper limb neurological deficits, developed and applied at Guttmann Institute (Barcelona, Spain). 9-HPT: 9-Hole Peg Test; Arm-A: Arm Activity Measure, section A; BBT: Box and Block Test; CIMT: Constraint Induced Movement Therapy; eCIMT: expanded CIMT; FM-UE: Fugl-Meyer Upper Extremity assessment; NIBS: Non-Invasive Brain Stimulation; SULCS: Stroke Upper Limb Capacity Scale. progress until upper limb functionality have been determined was considered as quick and useful entry evaluation; SULCS (no need to perform all the tasks), which is time-saving and score may be used as indication for further assessments (either avoids patient’s frustration or boredom for too difficult or too recommended and complementary) and therapeutic options. easy tasks; finally, tasks cover common functional activities, The present assessment algorithm has been developed at the like drinking from a glass or fastening buttons, which could Guttmann Institute (Barcelona, Spain) by physiotherapists already indicate goals for therapy. For these reasons, SULCS and occupational therapists, and is currently being used Frontiers in Neurology 14 frontiersin.org Boccuni et al. 10.3389/fneur.2022.939748 in the clinic as structured pipeline to evaluate upper limb - Robotics and FES: developers should consider the creation neurological deficits. of devices with both proximal and distal effectors, or hybrid devices (robotic/proximal and FES/distal) for the performance of reaching and grasping motor training. Conclusions and future perspectives - Virtual reality: developers should prioritize the automatization for the provision of intrinsic feedback, Upper limb neurorehabilitation is a difficult field of preferably as haptic/auditory feedback. intervention, that keeps challenging specialized healthcare - For any intervention: clinicians, technological developers providers to find tangible solutions to improve patients’ motor and researchers should find therapeutic solutions that allow outcomes and quality of life. The significant advancements of patients to train unassisted and unsupervised. The addition the last years are the result of a collective, international effort of independent therapy time on top of the formal patient- from thousands of passionate researchers and clinicians. It’s therapist session may represent the leading strategy to now essential to put research findings into practice, to provide provide high volume of training, distributed throughout the patients with the best opportunities of regaining functionality day, and economically sustainable in the long term. and independency. - Personalized interventions: perform a comprehensive For the sake of synthesis, we try to provide a evaluation of both objective neurological deficits and list of specific recommendations for clinical practice, patient’s perspective to develop tailored therapeutic goals technological developments, and future research on upper and personalized interventions. limb neurorehabilitation: - Patient-therapist session: consider two main phases: shaping and task practice. Shaping has the main goal of performing Author contributions a great number of repetitions in a short time frame, typically singular components of a functional task, preferably trained LB and JT conceived the original idea and drafted the first in an engaging, variable, and challenging way; enough time version of the manuscript. All authors provided substancial should be dedicated to this section, at least half of the total contributions and approved the submitted version. therapy time. Task practice should be performed as the final part of the session, to capitalize what was done in the previous phase for the relearning of a whole arm functional Funding activity. A third phase that was not mentioned previously in this article but nonetheless should be considered, The authors affiliated to Institut Guttmann disclosed is preparation. Preparation means daily briefing, body receipt of the following financial supports for the research, awareness and physical techniques to ensure proper stability authorship, and publication of this article: Programa Joan of the proximal segments and mobility of the distal Ribas Araquistain de Investigación, Innovación Terapéutica components, before shaping and task practice; preparation en Prehabilitación, Rehabilitación, Abordaje integral de las might require more time at the beginning of the rehabilitation secuelas de Tumores cerebrales from Fundaciò Joan Ribas program but should be gradually reduced as soon as the Araquistain (Reference Project 2020.330), Assaig controlat patient progresses, and in any case contained within one aleatori de l’efecte potenciador de l’estimulació transcranial third (or less) of the total therapy time, to prioritize de soroll aleatori (tRNS) en la rehabilitació cognitiva dels motor practice. pacients amb lesió cerebral traumàtica from Fundaciò La Maratò - Before/during motor task practice: consider motor imagery De TV3 Convocatòria d’ajuts projectes de recerca en Ictus and somatosensory electrical stimulation to prime motor i Lesions Medullars i Cerebrals traumàtiques 2017 (reference learning acquisition. For motor imagery, consider the project 201735.10), BBHI, Barcelona Brain Health Initiative development of audio tracks that patients can listen to while from Fundaciò Bancària La Caixa. resting in a quiet room. If you are using a FES device during the patient-therapist session, consider the possibility of modulating the intensity of the stimulation above the Conflict of interest motor threshold for movement production, but remaining between the sensory and motor threshold during rest periods. The authors declare that the research was conducted in - After motor task practice: consider aerobic training the absence of any commercial or financial relationships to enhance motor learning consolidation, and for that could be construed as a potential conflict cardiovascular benefits. of interest. Frontiers in Neurology 15 frontiersin.org Boccuni et al. 10.3389/fneur.2022.939748 Publisher’s note organizations, or those of the publisher, the editors and the reviewers. 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