Modulation of spinal circuits following phase-dependent electrical stimulation of afferent pathways.

Objective.Peripheral electrical stimulation (PES) of afferent pathways is a tool commonly used to induce neural adaptations in some neural disorders such as pathological tremor or stroke. However, the neuromodulatory effects of stimulation interventions synchronized with physiological activity (closed-loop strategies) have been scarcely researched in the upper-limb. Here, the short-term spinal effects of a 20-minute stimulation protocol where afferent pathways were stimulated with a closed-loop strategy named selective and adaptive timely stimulation (SATS) were explored in 11 healthy subjects.Approach. SATS was applied to the radial nerve in-phase (INP) or out-of-phase (OOP) with respect to the muscle activity of the extensor carpi radialis (ECR). The neural adaptations at the spinal cord level were assessed for the flexor carpi radialis (FCR) by measuring disynaptic Group I inhibition, Ia presynaptic inhibition, Ib facilitation from the H-reflex and estimation of the neural drive before, immediately after, and 30 minutes after the intervention.Main results.SATS strategy delivered electrical stimulation synchronized with the real-time muscle activity measured, with an average delay of 17 ± 8 ms. SATS-INP induced increased disynaptic Group I inhibition (77 ± 23% of baseline conditioned FCR H-reflex), while SATS-OOP elicited the opposite effect (125 ± 46% of baseline conditioned FCR H-reflex). Some of the subjects maintained the changes after 30 minutes. No other significant changes were found for the rest of measurements.Significance.These results suggest that the short-term modulatory effects of phase-dependent PES occur at specific targeted spinal pathways for the wrist muscles in healthy individuals. Importantly, timely recruitment of afferent pathways synchronized with specific muscle activity is a fundamental principle that shall be considered when tailoring PES protocols to modulate specific neural circuits. (NCT number 04501133).

Classification of Kinematic and Electromyographic Signals Associated with Pathological Tremor Using Machine and Deep Learning.

Peripheral Electrical Stimulation (PES) of afferent pathways has received increased interest as a solution to reduce pathological tremors with minimal side effects. Closed-loop PES systems might present some advantages in reducing tremors, but further developments are required in order to reliably detect pathological tremors to accurately enable the stimulation only if a tremor is present. This study explores different machine learning (K-Nearest Neighbors, Random Forest and Support Vector Machines) and deep learning (Long Short-Term Memory neural networks) models in order to provide a binary (Tremor; No Tremor) classification of kinematic (angle displacement) and electromyography (EMG) signals recorded from patients diagnosed with essential tremors and healthy subjects. Three types of signal sequences without any feature extraction were used as inputs for the classifiers: kinematics (wrist flexion-extension angle), raw EMG and EMG envelopes from wrist flexor and extensor muscles. All the models showed high classification scores (Tremor vs. No Tremor) for the different input data modalities, ranging from 0.8 to 0.99 for the f1 score. The LSTM models achieved 0.98 f1 scores for the classification of raw EMG signals, showing high potential to detect tremors without any processed features or preliminary information. These models may be explored in real-time closed-loop PES strategies to detect tremors and enable stimulation with minimal signal processing steps.

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.

Non-invasive electrical stimulation of peripheral nerves for the management of tremor.

Pathological tremor in patients with essential tremor and Parkinsons disease is typically treated using medication or neurosurgical interventions. There is a widely recognized need for new treatments that avoid the side effects of current medications and do not carry the risks of surgical interventions. Building on decades of research and engineering development, non-invasive electrical stimulation of peripheral nerves has emerged as a safe and effective strategy for reducing pathologic tremor in essential tremor. This review surveys the peripheral electrical stimulation (PES) literature and summarizes effectiveness, safety, clinical translatability, and hypothesized tremor-reduction mechanisms of various PES approaches. The review also proposes guidelines for assessing tremor in the context of evaluating new therapies that combine the strengths of clinician assessments, patient evaluations, and novel motion sensing technology. The review concludes with a summary of future directions for PES, including expanding clinical access for patients with Parkinson's disease and leveraging large, at-home datasets to learn more about tremor physiology and treatment effect that will better characterize the state of tremor management and accelerate discovery of new therapies. Growing evidence suggests that non-invasive electrical stimulation of afferent neural pathways provides a viable new option for management of pathological tremor, with one specific PES therapy cleared for prescription and home use, suggesting that PES be considered along with medication and neurosurgical interventions for treatment of tremor. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh.

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.

Peripheral electrical stimulation to reduce pathological tremor: a review.

Interventions to reduce tremor in essential tremor (ET) and Parkinson's disease (PD) clinical populations often utilize pharmacological or surgical therapies. However, there can be significant side effects, decline in effectiveness over time, or clinical contraindications for these interventions. Therefore, alternative approaches must be considered and developed. Some non-pharmacological strategies include assistive devices, orthoses and mechanical loading of the tremorgenic limb, while others propose peripheral electrical stimulation. Specifically, peripheral electrical stimulation encompasses strategies that activate motor and sensory pathways to evoke muscle contractions and impact sensorimotor function. Numerous studies report the efficacy of peripheral electrical stimulation to alter tremor generation, thereby opening new perspectives for both short- and long-term tremor reduction. Therefore, it is timely to explore this promising modality in a comprehensive review. In this review, we analyzed 27 studies that reported the use of peripheral electrical stimulation to reduce tremor and discuss various considerations regarding peripheral electrical stimulation: the stimulation strategies and parameters, electrodes, experimental designs, results, and mechanisms hypothesized to reduce tremor. From our review, we identified a high degree of disparity across studies with regard to stimulation patterns, experimental designs and methods of assessing tremor. Having standardized experimental methodology is a critical step in the field and is needed in order to accurately compare results across studies. With this review, we explore peripheral electrical stimulation as an intervention for tremor reduction, identify the limitations and benefits of the current state-of-the-art studies, and provide ideas to guide the development of novel approaches based on the neural circuitries and mechanical properties implied in tremor generation.

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 Marañón 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.

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

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) and above (> 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; maximum peak of inhibition was 45 ± 7% for ECR and 44 ± 13% for FCR when using 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.