Noninvasive Modalities Used in Spinal Cord Injury Rehabilitation

In the past three decades, research on plasticity after spinal cord injury (SCI) has led to a gradual shift in SCI rehabilitation: the former focus on learning compensatory strategies changed to functional neurorecovery, that is, promoting restoration of function through the use of affected limbs. This paradigm shift contributed to the development of technology-based interventions aiming to promote neurorecovery through repetitive training. This chapter presents an overview of a range of noninvasive modalities that have been used in rehabilitation after SCI. Among others, we present repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), surface electrical stimulation tools such as transcutaneous electrical spinal cord stimulation (tcSCS), transcutaneous electrical nerve stimulation (TENS), and functional electrical stimulation (FES), as well as its integration with cycling training and assistive robotic devices. The most recent results attained and the potential relevance of these new techniques to strengthen the efficacy of the residual neuronal pathways and improve spasticity are also presented. Future efforts toward the widespread clinical application of these modalities include more advances in the technology, together with the knowledge obtained from basic research and clinical trials. This can ultimately lead to novel customized interventions that meet specific needs of SCI patients

Prediction of Pathological Tremor Signals Using Long Short-Term Memory Neural Networks

Previous implementations of closed-loop peripheral electrical stimulation (PES) strategies have provided evidence about the effect of the stimulation timing on tremor reduction. However, these strategies have used traditional signal processing techniques that only consider phase prediction and might not model the non-stationary behavior of tremor. Here, we tested the use of long short-term memory (LSTM) neural networks to predict tremor signals using kinematic data recorded from Essential Tremor (ET) patients. A dataset comprising wrist flexion-extension data from 12 ET patients was pre-processed to feed the predictors. A total of 180 models resulting from the combination of network (neurons and layers of the LSTM networks, length of the input sequence and prediction horizon) and training parameters (learning rate) were trained, validated and tested. Predicted tremor signals using LSTM-based models presented high correlation values (from 0.709 to 0.998) with the expected values, with a phase delay between the predicted and real signals below 15 ms, which corresponds approximately to 7.5% of a tremor cycle. The prediction horizon was the parameter with a higher impact on the prediction performance. The proposed LSTM-based models were capable of predicting both phase and amplitude of tremor signals outperforming results from previous studies (32 - 56% decreased phase prediction error compared to the out-of-phase method), which might provide a more robust PES-based closed-loop control applied to PES-based tremor reduction.The authors would like to thank Cristina Montero Pardo for illustrations from Fig. 1 and the patients from Gregorio Marañón Hospital who voluntarily participated in this study

Intramuscular EMG-driven Musculoskeletal Modelling: Towards Implanted Muscle Interfacing in Spinal Cord Injury Patients

Objective: Surface EMG-driven modelling has been proposed as a means to control assistive devices by estimating joint torques. Implanted EMG sensors have several advantages over wearable sensors but provide a more localized information on muscle activity, which may impact torque estimates. Here, we tested and compared the use of surface and intramuscular EMG measurements for the estimation of required assistive joint torques using EMG driven modelling. Methods: Four healthy subjects and three incomplete spinal cord injury (SCI) patients performed walking trials at varying speeds. Motion capture marker trajectories, surface and intramuscular EMG, and ground reaction forces were measured concurrently. Subject-specific musculoskeletal models were developed for all subjects, and inverse dynamics analysis was performed for all individual trials. EMG-driven modelling based joint torque estimates were obtained from surface and intramuscular EMG. Results: The correlation between the experimental and predicted joint torques was similar when using intramuscular or surface EMG as input to the EMG-driven modelling estimator in both healthy individuals and patients. Conclusion: We have provided the first comparison of non-invasive and implanted EMG sensors as input signals for torque estimates in healthy individuals and SCI patients. Significance: Implanted EMG sensors have the potential to be used as a reliable input for assistive exoskeleton joint torque actuation

Intramuscular Stimulation of Muscle Afferents Attains Prolonged Tremor Reduction in Essential Tremor Patients

This study proposes and clinically tests intramuscular electrical stimulation below motor threshold to achieve prolonged reduction of wrist flexion/extension tremor in Essential Tremor (ET) patients. The developed system consisted of an intramuscular thin-film electrode structure that included both stimulation and electromyography (EMG) recording electrodes, and a control algorithm for the timing of intramuscular stimulation based on EMG (closed-loop stimulation). Data were recorded from nine ET patients with wrist flexion/extension tremor recruited from the Gregorio Mara\uf1\uf3n Hospital (Madrid, Spain). Patients participated in two experimental sessions comprising: 1) sensory stimulation of wrist flexors/extensors via thin-film multichannel intramuscular electrodes; and 2) surface stimulation of the nerves innervating the same target muscles. For each session, four of these patients underwent random 60-s trials of two stimulation strategies for each target muscle: 1) selective and adaptive timely stimulation (SATS) - based on EMG of the antagonist muscle; and 2) continuous stimulation (CON) of target muscles. Two patients underwent SATS stimulation trials alone while the other three underwent CON stimulation trials alone in each session. Kinematics of wrist, elbow, and shoulder, together with clinical scales, were used to assess tremor before, right after, and 24 h after each session. Intramuscular SATS achieved, on average, 32% acute (during stimulation) tremor reduction on each trial, while continuous stimulation augmented tremorgenic activity. Furthermore, tremor reduction was significantly higher using intramuscular than surface stimulation. Prolonged reduction of tremor amplitude (24 h after the experiment) was observed in four patients. These results showed acute and prolonged (24 h) tremor reduction using a minimally invasive neurostimulation technology based on SATS of primary sensory afferents of wrist muscles. This strategy might open the possibility of an alternative therapeutic approach for ET patients

Reduction of Pathological Tremor in Essential Tremor Patients Through Peripheral Electrical Stimulation of Afferent Pathways

Essential tremor (ET) is the leading cause of pathological tremor, the most common movement disorder in the adult population. This involuntary movement of one or more parts of the body can become a disabling condition for the execution of activities of daily living, which has a signifcant impact on patients’ quality of life. Nowadays, there is no cure for ET and current treatments have limited effcacy, considerable adverse effects or they are not accessible to a large part of the population. Therefore, there is a need to develop effective and affordable solutions for the management of ET. Peripheral electrical stimulation (PES) of afferent (sensory) pathways is an emerging technique with promising results for the reduction of pathological tremor due to its usability and limited adverse effects. Despite early indications of effcacy, it is necessary to further characterize the physiological effects of PES as a tool to modulate the nervous system, as well as its potential effcacy in reducing tremor. The main objective of this PhD thesis was the development of a technique based on PES of afferent pathways to reduce pathological tremor in ET patients by modulating neural pathways involved in the tremor circuits. To achieve this goal, a stepwise approach was employed. First, a comprehensive review of the state of the art of PES techniques applied to reduce pathological tremor was performed, which allowed the identifcation of methodologies, results, advantages and limitations of the solutions proposed in scientifc literature. This knowledge presented the physiological and technical bases needed to develop the consequent studies of this thesis. The frst study of this thesis demonstrated the hypothesis that stimulation of the afferent pathways of the antagonist muscle can produce inhibition of voluntary muscle activity in the wrist muscles in healthy subjects. Inhibition occurred at stimulation intensities above and below motor threshold, and the latency of this inhibition was consistent with inhibitory spinal circuits. These results added more evidence that justify the use of afferent stimulation below the motor threshold of the antagonist muscle as a tool to acutely inhibit tremor activity. The second study presented the development and validation of a closed-loop stimulation strategy based on electromyography named Selective and Adaptive Timely Stimulation (SATS) of afferent pathways. The short-term neuromodulatory effects at the spinal level were tested after the stimulation was applied in-phase or out-of-phase with muscle activity in healthy subjects while they replicated pathological wrist tremor movements for 20 minutes. The results showed that the SATS strategy was able to deliver stimulation synchronized with muscle activity with high temporal precision. Additionally, the inhibitory spinal circuit responsible for the inhibition of the antagonist muscle was potentiated when the stimulation was applied in-phase with the muscle activity, whereas the out-of-phase stimulation produced a depression on the same inhibitory spinal circuit. Overall, this study demonstrated the feasibility of the SATS strategy as a tool for modulating spinal circuits, and the importance of synchronizing stimulation with physiological activity to induce specifc adaptations in the nervous system. Finally, the SATS strategy was tested on a cohort of ET patients. To demonstrate the tremor reduction effects associated with the SATS strategy, patients received this stimulation applied out-of-phase with the tremor activity (stimulation of the antagonist muscle), or continuous open-loop stimulation. Both strategies were tested in two experimental sessions using minimally-invasive intramuscular electrodes or surface electrodes. The results showed that the SATS strategy applied through intramuscular electrodes acutely reduces tremor (while stimulation was active), while continuous stimulation did not reduce tremor. Furthermore, a short-term tremor reduction effect was reported at the end of the experimental session for patients receiving SATS applied with intramuscular electrodes. For some patients, this tremor reduction was maintained for 24 hours after the session. In conclusion, this PhD thesis presents evidence on the characterization and validation of PES of afferent pathways synchronized with physiological activity as a tool to reduce pathological tremor in ET patients. These advances may have a signifcant impact on the quality of life of patients, as they lay the foundations for the development of accessible neuroprostheses with minimal side effects for the effective acute and therapeutic treatment of pathological tremor. ----------RESUMEN---------- El temblor esencial (ET) es la principal causa de temblor patológico, el trastorno de movimiento con mayor incidencia en la población adulta. Este movimiento involuntario de una o más partes del cuerpo puede llegar a resultar incapacitante para el desarrollo de tareas cotidianas, lo cual tiene un importante impacto en la calidad de vida de los pacientes. Actualmente no existe cura para el TE y los tratamientos actuales tienen limitada eficacia, considerables efectos adversos o no son accesibles para una gran parte de la población. Por ello es necesario el desarrollo de soluciones y eficaces y accesibles para el manejo del TE. La estimulación eléctrica periférica (EEP) de las vías aferentes (sensoriales) es una técnica emergente con resultados prometedores para la reducción del temblor patológico debido a sus limitados efectos adversos y usabilidad. A pesar de los primeros indicios de eficacia, es necesario profundizar en la caracterización de los efectos fisiológicos de la EEP como herramienta para modular el sistema nervioso, así como su potencial eficacia para reducir el temblor. El objetivo principal de esta tesis doctoral fue el desarrollo de una técnica de EEP de las vías aferentes para reducir el temblor patológico en pacientes de TE mediante la modulación de los circuitos neuronales afectados por temblor. Para conseguir dicho objetivo, se ha empleado un enfoque gradual. En primer lugar, se realizó una revisión exhaustiva sobre el estado del arte de las técnicas de EEP aplicadas a la reducción de temblor patológico, lo cual permitió identificar las metodologías, los resultados, las ventajas y limitaciones de las soluciones propuestas en la literatura científica. Este conocimiento presentó las bases de conocimiento fisiológicas y técnicas necesarias para el desarrollo de los siguientes estudios de esta tesis. En el primer estudio de esta tesis se demostró la hipótesis de que la estimulación de las vías aferentes del músculo antagonista puede producir la inhibición de la actividad muscular voluntaria en los músculos de la muñeca en sujetos sanos. La inhibición se produjo con intensidades de estimulación por encima y por debajo del umbral motor, y la latencia de esta inhibición es compatible con los circuitos espinales de inhibición recíproca. Estos resultados justifican la utilización de la estimulación aferente por debajo del umbral motor del músculo antagonista como herramienta para inhibir de forma aguda la actividad del temblor. A continuación, se desarrolló una estrategia de estimulación selectiva y adaptativa de las vías aferentes de lazo cerrado (SATS) basada en señales de electromiografía. Los efectos neuromodulatorios a nivel espinal de esta estrategia fueron testados cuando la estimulación fue aplicada en fase o en contrafase con la actividad muscular en sujetos sanos mientras estos replicaban movimientos patológicos de temblor de muñeca durante 20 minutos. Los resultados mostraron que la estrategia SATS fue capaz de aplicar estimulación sincronizada con la actividad muscular con alta precisión temporal. Asimismo, se produjo una potenciación de la inhibición del músculo antagonista cuando la estimulación fue aplicada en fase, mientras que la estimulación en contrafase produjo una depresión de dicha inhibición. En su conjunto, este estudio demostró la viabilidad de la estrategia SATS como herramienta de modulación de los circuitos espinales, así como la importancia de la sincronización de la estimulación con la actividad fisiológica para inducir cambios específicos en el sistema nervioso, justificando así su utilización para la reducción de temblor patológico. Finalmente, la estrategia SATS fue testada en pacientes con TE. Para demostrar los efectos de reducción de temblor asociados a la estrategia SATS, los pacientes recibieron esta estimulación aplicada en contrafase con la actividad de temblor (estimulación del músculo antagonista), así como una estimulación continua de lazo abierto. Ambas fueron aplicadas mediante electrodos intramusculares mínimamente invasivos en una sesión, y mediante electrodos superficiales en otra. Los resultados mostraron que la estrategia SATS aplicada mediante electrodos intramusculares consiguió reducir el temblor agudo (mientras la estimulación está activa), mientras que la estimulación continua no redujo el temblor. Igualmente, se reportó una reducción de temblor a corto plazo al finalizar la sesión experimental que para aquellos pacientes que recibieron la estimulación SATS aplicada con electrodos intramusculares. En algunos pacientes esta reducción de temblor se mantuvo 24 horas después de la sesión experimental. En conclusión, esta tesis doctoral presenta evidencias sobre la caracterización y validación de la EEP de las vías aferentes sincronizadas con la actividad fisiológica como herramienta de reducción del temblor patológico en pacientes con TE. Estos avances pueden tener un gran impacto en la calidad de vida de los pacientes, ya que sientan las bases para el desarrollo de neuroprótesis accesibles y con mínimos efectos secundarios para el tratamiento eficaz agudo y terapéutico del temblor patológico

Noninvasive Modalities Used in Spinal Cord Injury Rehabilitation

In the past three decades, research on plasticity after spinal cord injury (SCI) has led to a gradual shift in SCI rehabilitation: the former focus on learning compensatory strategies changed to functional neurorecovery, that is, promoting restoration of function through the use of affected limbs. This paradigm shift contributed to the development of technology-based interventions aiming to promote neurorecovery through repetitive training. This chapter presents an overview of a range of noninvasive modalities that have been used in rehabilitation after SCI. Among others, we present repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), surface electrical stimulation tools such as transcutaneous electrical spinal cord stimulation (tcSCS), transcutaneous electrical nerve stimulation (TENS), and functional electrical stimulation (FES), as well as its integration with cycling training and assistive robotic devices. The most recent results attained and the potential relevance of these new techniques to strengthen the efficacy of the residual neuronal pathways and improve spasticity are also presented. Future efforts toward the widespread clinical application of these modalities include more advances in the technology, together with the knowledge obtained from basic research and clinical trials. This can ultimately lead to novel customized interventions that meet specific needs of SCI patients.This work was funded by the European Union’s Horizon 2020 research and innovation programme (Project EXTEND—Bidirectional Hyper-Connected Neural System) under grant agreement No 779982 and by the EFOP-3.6.1-16-2016-00004 grant

Modulation of reciprocal inhibition at the wrist as a neurophysiological correlate of tremor suppression: a pilot healthy subject study

Trabajo presentado en EMBC’19 - 41st Annual International Conference of the IEEE Engineering in Medicine and Biology Society en Berlin, Alemania, el 23 de Julio de 2019.It has been shown that Ia afferents inhibit muscle activity of the ipsilateral antagonist, a mechanism known as reciprocal inhibition. Stimulation of these afferents may be explored for the therapeutic reduction of pathological tremor (Essential Tremor or due Parkinson's Disease, for example). However, only a few studies have investigated reciprocal inhibition of wrist flexor / extensor motor control. The main goal of this study was to characterize reciprocal inhibition of wrist flexors / extensors by applying surface electrical stimulation to the radial and median nerves, respectively. Firstly, the direct (M) and monosynaptic (H) reflex responses to increasing median and radial nerve stimulation were recorded to characterize the recruitment curve of the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles, respectively. Based on the recruitment curve data, we then stimulated the median and radial nerves below ( MT) motor threshold (MT) during a submaximal isometric task to assess the amount of inhibition on ECR and FCR antagonist muscles, respectively. The stimulation of both nerves produced a long-duration inhibition of the antagonist motoneuron pool activity. On average, maximum peak of inhibition was 27 ± 6% for ECR and 32 ± 9% for FCR with stimulation MT. These results validate this neurophysiological technique that demonstrates a mechanism similar to classical reciprocal Ia inhibition reported for other limb joints and that can be used to benchmark strategies to suppress pathological tremor

Control method for a neuroprosthetic device for the reduction of a pathological tremors

The invention relates to a control method for a neuroprosthetic device, allowing to monitor and reduce pathological tremors in users via the stimulation of the peripheral muscles and modulation of the afferent pathways.Peer reviewedConsejo Superior de Investigaciones Científicas (CSIC), Imperial College Innovations Limited (ICIL). Fundación para la investigación biomédica del Hospital Gregorio Marañón (FIBHGM)A1 Solicitud de patente con informe sobre el estado de la técnic