Protein interactome of 3',5'-cAMP reveals its role in regulating the actin cytoskeleton.

Identification of protein interactors is ideally suited for the functional characterization of small molecules. 3',5'-cAMP is an evolutionary ancient signaling metabolite largely uncharacterized in plants. To tap into the physiological roles of 3',5'-cAMP, we used a chemo-proteomics approach, thermal proteome profiling (TPP), for the unbiased identification of 3',5'-cAMP protein targets. TPP measures shifts in the protein thermal stability upon ligand binding. Comprehensive proteomics analysis yielded a list of 51 proteins significantly altered in their thermal stability upon incubation with 3',5'-cAMP. The list contained metabolic enzymes, ribosomal subunits, translation initiation factors, and proteins associated with the regulation of plant growth such as CELL DIVISION CYCLE 48. To functionally validate obtained results, we focused on the role of 3',5'-cAMP in regulating the actin cytoskeleton suggested by the presence of actin among the 51 identified proteins. 3',5'-cAMP supplementation affected actin organization by inducing actin-bundling. Consistent with these results, the increase in 3',5'-cAMP levels, obtained either by feeding or by chemical modulation of 3',5'-cAMP metabolism, was sufficient to partially rescue the short hypocotyl phenotype of the actin2 actin7 mutant, severely compromised in actin level. The observed rescue was specific to 3',5'-cAMP, as demonstrated using a positional isomer 2',3'-cAMP, and true for the nanomolar 3',5'-cAMP concentrations reported for plant cells. In vitro characterization of the 3',5'-cAMP-actin pairing argues against a direct interaction between actin and 3',5'-cAMP. Alternative mechanisms by which 3',5'-cAMP would affect actin dynamics, such as by interfering with calcium signaling, are discussed. In summary, our work provides a specific resource, 3',5'-cAMP interactome, as well as functional insight into 3',5'-cAMP-mediated regulation in plants.

A Robot-Assisted Therapy to Increase Muscle Strength in Hemiplegic Gait Rehabilitation.

This study examines the feasibility of using a robot-assisted therapy methodology based on the Bobath concept to perform exercises applied in conventional therapy for gait rehabilitation in stroke patients. The aim of the therapy is to improve postural control and movement through exercises based on repetitive active-assisted joint mobilization, which is expected to produce strength changes in the lower limbs. As therapy progresses, robotic assistance is gradually reduced and the patient's burden increases with the goal of achieving a certain degree of independence. The relationship between force and range of motion led to the analysis of both parameters of interest. The study included 23 volunteers who performed 24 sessions, 2 sessions per week for 12 weeks, each lasting about 1 h. The results showed a significant increase in hip abduction and knee flexion strength on both sides, although there was a general trend of increased strength in all joints. However, the range of motion at the hip and ankle joints was reduced. The usefulness of this platform for transferring exercises from conventional to robot-assisted therapies was demonstrated, as well as the benefits that can be obtained in muscle strength training. However, it is suggested to complement the applied therapy with exercises for the maintenance and improvement of the range of motion.

Adaptive multichannel FES neuroprosthesis with learning control and automatic gait assessment.

BACKGROUND: FES (Functional Electrical Stimulation) neuroprostheses have long been a permanent feature in the rehabilitation and gait support of people who had a stroke or have a Spinal Cord Injury (SCI). Over time the well-known foot switch triggered drop foot neuroprosthesis, was extended to a multichannel full-leg support neuroprosthesis enabling improved support and rehabilitation. However, these neuroprostheses had to be manually tuned and could not adapt to the persons' individual needs. In recent research, a learning controller was added to the drop foot neuroprosthesis, so that the full stimulation pattern during the swing phase could be adapted by measuring the joint angles of previous steps. METHODS: The aim of this research is to begin developing a learning full-leg supporting neuroprosthesis, which controls the antagonistic muscle pairs for knee flexion and extension, as well as for ankle joint dorsi- and plantarflexion during all gait phases. A method was established that allows a continuous assessment of knee and foot joint angles with every step. This method can warp the physiological joint angles of healthy subjects to match the individual pathological gait of the subject and thus allows a direct comparison of the two. A new kind of Iterative Learning Controller (ILC) is proposed which works independent of the step duration of the individual and uses physiological joint angle reference bands. RESULTS: In a first test with four people with an incomplete SCI, the results showed that the proposed neuroprosthesis was able to generate individually fitted stimulation patterns for three of the participants. The other participant was more severely affected and had to be excluded due to the resulting false triggering of the gait phase detection. For two of the three remaining participants, a slight improvement in the average foot angles could be observed, for one participant slight improvements in the averaged knee angles. These improvements where in the range of 4circat the times of peak dorsiflexion, peak plantarflexion, or peak knee flexion. CONCLUSIONS: Direct adaptation to the current gait of the participants could be achieved with the proposed method. The preliminary first test with people with a SCI showed that the neuroprosthesis can generate individual stimulation patterns. The sensitivity to the knee angle reset, timing problems in participants with significant gait fluctuations, and the automatic ILC gain tuning are remaining issues that need be addressed. Subsequently, future studies should compare the improved, long-term rehabilitation effects of the here presented neuroprosthesis, with conventional multichannel FES neuroprostheses.

Advances in neuroprosthetic management of foot drop: a review.

This paper reviews the technological advances and clinical results obtained in the neuroprosthetic management of foot drop. Functional electrical stimulation has been widely applied owing to its corrective abilities in patients suffering from a stroke, multiple sclerosis, or spinal cord injury among other pathologies. This review aims at identifying the progress made in this area over the last two decades, addressing two main questions: What is the status of neuroprosthetic technology in terms of architecture, sensorization, and control algorithms?. What is the current evidence on its functional and clinical efficacy? The results reveal the importance of systems capable of self-adjustment and the need for closed-loop control systems to adequately modulate assistance in individual conditions. Other advanced strategies, such as combining variable and constant frequency pulses, could also play an important role in reducing fatigue and obtaining better therapeutic results. The field not only would benefit from a deeper understanding of the kinematic, kinetic and neuromuscular implications and effects of more promising assistance strategies, but also there is a clear lack of long-term clinical studies addressing the therapeutic potential of these systems. This review paper provides an overview of current system design and control architectures choices with regard to their clinical effectiveness. Shortcomings and recommendations for future directions are identified.

Influences of the biofeedback content on robotic post-stroke gait rehabilitation: electromyographic vs joint torque biofeedback.

BACKGROUND: Add-on robot-mediated therapy has proven to be more effective than conventional therapy alone in post-stroke gait rehabilitation. Such robot-mediated interventions routinely use also visual biofeedback tools. A better understanding of biofeedback content effects when used for robotic locomotor training may improve the rehabilitation process and outcomes. METHODS: This randomized cross-over pilot trial aimed to address the possible impact of different biofeedback contents on patients' performance and experience during Lokomat training, by comparing a novel biofeedback based on online biological electromyographic information (EMGb) versus the commercial joint torque biofeedback (Rb) in sub-acute non ambulatory patients. 12 patients were randomized into two treatment groups, A and B, based on two different biofeedback training. For both groups, study protocol consisted of 12 Lokomat sessions, 6 for each biofeedback condition, 40 min each, 3 sessions per week of frequency. All patients performed Lokomat trainings as an add-on therapy to the conventional one that was the same for both groups and consisted of 40 min per day, 5 days per week. The primary outcome was the Modified Ashworth Spasticity Scale, and secondary outcomes included clinical, neurological, mechanical, and personal experience variables collected before and after each biofeedback training. RESULTS: Lokomat training significantly improved gait/daily living activity independence and trunk control, nevertheless, different effects due to biofeedback content were remarked. EMGb was more effective to reduce spasticity and improve muscle force at the ankle, knee and hip joints. Robot data suggest that Rb induces more adaptation to robotic movements than EMGb. Furthermore, Rb was perceived less demanding than EMGb, even though patient motivation was higher for EMGb. Robot was perceived to be effective, easy to use, reliable and safe: acceptability was rated as very high by all patients. CONCLUSIONS: Specific effects can be related to biofeedback content: when muscular-based information is used, a more direct effect on lower limb spasticity and muscle activity is evidenced. In a similar manner, when biofeedback treatment is based on joint torque data, a higher patient compliance effect in terms of force exerted is achieved. Subjects who underwent EMGb seemed to be more motivated than those treated with Rb.

Boosting the traditional physiotherapist approach for stroke spasticity using a sensorized ankle foot orthosis: a pilot study.

BACKGROUND: Spasticity is a motor disorder that is commonly treated manually by a physical therapist (PhT) stretching the muscles. Recent data on learning have demonstrated the importance of human-to-human interaction in improving rehabilitation: cooperative motor behavior engages specific areas of the motor system compared with execution of a task alone. OBJECTIVES: We hypothesize that PhT-guided therapy that involves active collaboration with the patient (Pt) through shared biomechanical visual biofeedback (vBFB) positively impacts learning and performance by the Pt during ankle spasticity treatment. A sensorized ankle foot orthosis (AFO) was developed to provide online quantitative data of joint range of motion (ROM), angular velocity, and electromyographic activity to the PhT and Pt during the treatment of ankle spasticity. METHODS: Randomized controlled clinical trial. Ten subacute stroke inpatients, randomized into experimental (EXP) and control (CTRL) groups, underwent six weeks of daily treatment. The EXP group was treated with an active AFO, and the CTRL group was given an inactive AFO. Spasticity, ankle ROM, ankle active and passive joint speed, and coactivation index (CI) were assessed at enrollment and after 15-30 sessions. RESULTS: Spasticity and CI (p < 0.005) decreased significantly after training only in the EXP group, in association with a significant rise in active joint speed and active ROM (p < 0.05). Improvements in spasticity (p < 0.05), active joint speed (p < 0.001), and CI (p < 0.001) after treatment differed between the EXP and CTRL groups. CONCLUSIONS: PhT-Pt sharing of exercise information, provided by joint sensorization and vBFB, improved the efficacy of the conventional approach for treating ankle spasticity in subacute stroke Pts.

Advances in selective activation of muscles for non-invasive motor neuroprostheses.

Non-invasive neuroprosthetic (NP) technologies for movement compensation and rehabilitation remain with challenges for their clinical application. Two of those major challenges are selective activation of muscles and fatigue management. This review discusses how electrode arrays improve the efficiency and selectivity of functional electrical stimulation (FES) applied via transcutaneous electrodes. In this paper we review the principles and achievements during the last decade on techniques for artificial motor unit recruitment to improve the selective activation of muscles. We review the key factors affecting the outcome of muscle force production via multi-pad transcutaneous electrical stimulation and discuss how stimulation parameters can be set to optimize external activation of body segments. A detailed review of existing electrode array systems proposed by different research teams is also provided. Furthermore, a review of the targeted applications of existing electrode arrays for control of upper and lower limb NPs is provided. Eventually, last section demonstrates the potential of electrode arrays to overcome the major challenges of NPs for compensation and rehabilitation of patient-specific impairments.

Hybrid FES-robot cooperative control of ambulatory gait rehabilitation exoskeleton.

Robotic and functional electrical stimulation (FES) approaches are used for rehabilitation of walking impairment of spinal cord injured individuals. Although devices are commercially available, there are still issues that remain to be solved. Control of hybrid exoskeletons aims at blending robotic exoskeletons and electrical stimulation to overcome the drawbacks of each approach while preserving their advantages. Hybrid actuation and control have a considerable potential for walking rehabilitation but there is a need of novel control strategies of hybrid systems that adequately manage the balance between FES and robotic controllers. Combination of FES and robotic control is a challenging issue, due to the non-linear behavior of muscle under stimulation and the lack of developments in the field of hybrid control. In this article, a cooperative control strategy of a hybrid exoskeleton is presented. This strategy is designed to overcome the main disadvantages of muscular stimulation: electromechanical delay and change in muscle performance over time, and to balance muscular and robotic actuation during walking.Experimental results in healthy subjects show the ability of the hybrid FES-robot cooperative control to balance power contribution between exoskeleton and muscle stimulation. The robotic exoskeleton decreases assistance while adequate knee kinematics are guaranteed. A new technique to monitor muscle performance is employed, which allows to estimate muscle fatigue and implement muscle fatigue management strategies. Kinesis is therefore the first ambulatory hybrid exoskeleton that can effectively balance robotic and FES actuation during walking. This represents a new opportunity to implement new rehabilitation interventions to induce locomotor activity in patients with paraplegia.Acronym list: 10 mWT: ten meters walking test; 6 MWT: six minutes walking test; FSM: finite-state machine; t-FSM: time-domain FSM; c-FSM: cycle-domain FSM; FES: functional electrical stimulation; HKAFO: hip-knee-ankle-foot orthosis; ILC: iterative error-based learning control; MFE: muscle fatigue estimator; NILC: Normalized stimulation output from ILC controller; PID: Proportional-Integral-derivative Control; PW: Stimulation pulse width; QUEST: Quebec User Evaluation of Satisfaction with assistive Technology; SCI: Spinal cord injury; TTI: torque-time integral; VAS: Visual Analog Scale.

Review of hybrid exoskeletons to restore gait following spinal cord injury.

Different approaches are available to compensate gait in persons with spinal cord injury, including passive orthoses, functional electrical stimulation (FES), and robotic exoskeletons. However, several drawbacks arise from each specific approach. Orthotic gait is energy-demanding for the user and functionally ineffective. FES uses the muscles as natural actuators to generate gait, providing not only functional but also psychological benefits to the users. However, disadvantages are also related to the early appearance of muscle fatigue and the control of joint trajectories. Robotic exoskeletons that provide joint moment compensation or substitution to the body during walking have been developed in recent years. Significant advances have been achieved, but the technology itself is not mature yet because of many limitations related to both physical and cognitive interaction as well as portability and energy-management issues. Meanwhile, the combination of FES technology and exoskeletons has emerged as a promising approach to both gait compensation and rehabilitation, bringing together technologies, methods, and rehabilitation principles that can overcome the drawbacks of each individual approach. This article presents an overview of hybrid lower-limb exoskeletons, related technologies, and advances in actuation and control systems. Also, we highlight the functional assessment of individuals with spinal cord injury.

Neurorobotic and hybrid management of lower limb motor disorders: a review.

A neurobot (NR) is a mechatronic wearable robot that can be applied to drive a paralyzed limb. Through the application of controllable forces, a NR can assist, replace, or retrain a certain motor function. Robotic intervention in rehabilitation of motor disorders has a potential to improve traditional therapeutic interventions. Because of its flexibility, repeatability and quantifiability, NRs have been more and more applied in neurorehabilitation. Furthermore, combination of NRs with functional electrical stimulation/therapy constitutes a trend to overcome a number of practical limitations to widespread the application of NRs in clinical settings and motor control studies. In this review, we examine the motor learning principles, robotic control approaches and novel developments from studies with NRs and hybrid systems, with a focus on rehabilitation of the lower limbs.