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Pathological tremors are involuntary oscillatory movements which cannot be fully attenuated using conventional treatments. For this reason, several studies have investigated the use of neuromuscular electrical stimulation for tremor suppression. In a recent study, however, we found that electrical stimulation below the motor threshold also suppressed tremor, indicating involvement of afferent pathways. In this study, we further explored this possibility by systematically investigating how tremor suppression by afferent stimulation depends on the stimulation settings. In this way, we aimed at identifying the optimal stimulation strategy, as well as to elucidate the underlying physiological mechanisms of tremor suppression. Stimulation strategies varying the stimulation intensity and pulse timing were tested in nine tremor patients using either intramuscular or surface stimulation. Significant tremor suppression was observed in six patients (tremor suppression > 75% was observed in three patients) and the average optimal suppression level observed across all subjects was 52%. The efficiency for each stimulation setting, however, varied substantially across patients and it was not possible to identify a single set of stimulation parameters that yielded positive results in all patients. For example, tremor suppression was achieved both with stimulation delivered in an out-of-phase pattern with respect to the tremor, and with random timing of the stimulation. Overall, these results indicate that low-current stimulation of afferent fibers is a promising approach for tremor suppression, but that further research is required to identify how the effect can be maximized in the individual patient.

The pathophysiology of essential tremor (ET), the most common movement disorder, is not fully understood. We investigated which factors determine the variability in the phase difference between neural drives to antagonist muscles, a long-standing observation yet unexplained. We used a computational model to simulate the effects of different levels of voluntary and tremulous synaptic input to antagonistic motoneuron pools on the tremor. We compared these simulations to data from 11 human ET patients. In both analyses, the neural drive to muscle was represented as the pooled spike trains of several motor units, which provides an accurate representation of the common synaptic input to motoneurons. The simulations showed that, for each voluntary input level, the phase difference between neural drives to antagonist muscles is determined by the relative strength of the supraspinal tremor input to the motoneuron pools. In addition, when the supraspinal tremor input to one muscle was weak or absent, Ia afferents provided significant common tremor input due to passive stretch. The simulations predicted that without a voluntary drive (rest tremor) the neural drives would be more likely in phase, while a concurrent voluntary input (postural tremor) would lead more frequently to an out-of-phase pattern. The experimental results matched these predictions, showing a significant change in phase difference between postural and rest tremor. They also indicated that the common tremor input is always shared by the antagonistic motoneuron pools, in agreement with the simulations. Our results highlight that the interplay between supraspinal input and spinal afferents is relevant for tremor generation.

Objective. Pathological tremors are symptomatic to several neurological disorders that are difficult to differentiate and the way by which central oscillatory networks entrain tremorogenic contractions is unknown. We considered the alternative hypotheses that tremor arises from one oscillator (at the tremor frequency) or, as suggested by recent findings from the superimposition of two separate inputs (at the tremor frequency and twice that frequency). Approach. Assuming one central oscillatory network we estimated analytically the relative amplitude of the harmonics of the tremor frequency in the motor neuron output for different temporal behaviors of the oscillator. Next, we analyzed the bias in the relative harmonics amplitude introduced by superimposing oscillations at twice the tremor frequency. These findings were validated using experimental measurements of wrist angular velocity and surface electromyography (EMG) from 22 patients (11 essential tremor, 11 Parkinson's disease). The ensemble motor unit action potential trains identified from the EMG represented the neural drive to the muscles. Main results. The analytical results showed that the relative power of the tremor harmonics in the analytical models of the neural drive was determined by the variability and duration of the tremor bursts and the presence of the second oscillator biased this power towards higher values. The experimental findings accurately matched the analytical model assuming one oscillator, indicating a negligible functional role of secondary oscillatory inputs. Furthermore, a significant difference in the relative power of harmonics in the neural drive was found across the patient groups, suggesting a diagnostic value of this measure (classification accuracy: 86%). This diagnostic power decreased substantially when estimated from limb acceleration or the EMG. Signficance. The results indicate that the neural drive in pathological tremor is compatible with one central network providing n

Tremor in essential tremor (ET) is generated by pathological oscillations at 4 to 12 Hz, likely originating at cerebello-thalamo-cortical pathways. However, the way in which tremor is represented in the output of the spinal cord circuitries is largely unknown because of the difficulties in identifying the behavior of individual motor units from tremulous muscles. By using novel methods for the decomposition of multichannel surface EMG, we provide a systematic analysis of the discharge properties of motor units in 9 ET patients, with concurrent recordings of EEG activity. This analysis allowed inferring the contribution of common synaptic inputs to motor neurons in ET. Motor unit short-term synchronization was significantly greater in ET patients than in healthy subjects. Further, the strong association between the degree of synchronization and the peak in coherence between motor unit spike trains at the tremor frequency indicated that the high synchronization levels were generated mainly by common synaptic inputs specifically at the tremor frequency. The coherence between EEG and motor unit spike trains demonstrated the presence of common cortical input to the motor neurons at the tremor frequency. Nonetheless, the strength of this input was uncorrelated to the net common synaptic input at the tremor frequency, suggesting a contribution of spinal afferents or secondary supraspinal pathways in projecting common input at the tremor frequency. These results provide the first systematic analysis of the neural drive to the muscle in ET and elucidate some of its characteristics that determine the pathological tremulous muscle activity.

1534-4320 (c) 2014 IEEE.Tremor is one of the most prevalent movement disorders. There is a large proportion of patients (around 25%) in whom current treatments do not attain a significant tremor reduction. This paper proposes a tremor suppression strategy that detects tremor from the electromyographic signals of the muscles from which tremor originates and counteracts it by delivering electrical stimulation to the antagonist muscles in an out of phase manner. The detection was based on the Iterative Hilbert Transform and stimulation was delivered above the motor threshold (motor stimulation) and below the motor threshold (sensory stimulation). The system was tested on 6 patients with predominant wrist flexion/extension tremor (4 with Parkinson disease and 2 with Essential tremor) and led to an average tremor reduction in the range of 46-81% and 35-48% across 5 patients when using the motor and sensory stimulation, respectively. In one patient, the system did not attenuate tremor. These results demonstrate that tremor attenuation might be achieved by delivering electrical stimulation below the motor threshold, preventing muscle fatigue and discomfort for the patients, which sets the basis for the development of an alternative treatment for tremor

Tremor is the most prevalent movement disorder, and its incidence is increasing with aging. In spite of the numerous therapeutic solutions available, 65% of those suffering from upper limb tremor report serious difficulties during their daily living. This gives rise to research on different treatment alternatives, amongst which wearable robots that apply selective mechanical loads constitute an appealing approach. In this context, the current work presents a multimodal human-robot interface to drive a neuroprosthesis for tremor management. Our approach relies on the precise characterization of the tremor to modulate a functional electrical stimulation system that compensates for it. The neuroprosthesis is triggered by the detection of the intention to move derived from the analysis of electroencephalographic activity, which provides a natural interface with the user. When a prediction is delivered, surface electromyography serves to detect the actual onset of the tremor in the presence of volitional activity. This information in turn triggers the stimulation, which relies on tremor parameters-amplitude and frequency-derived from a pair of inertial sensors that record the kinematics of the affected joint. Surface electromyography also yields a first characterization of the tremor, together with precise information on the preferred stimulation site. Apart from allowing for an optimized performance of the system, our multimodal approach permits the implementation of redundant methods to both enhance the reliability of the system and adapt to the specific needs of different users. Results with a representative group of patients illustrate the performance of the interface presented here and demonstrate its feasibility.

In spite of decades of intense research, pathological tremors still constitute unknown disorders. This study addresses, based on a multi-scale model, the behavior of an entire pool of motor neurons in tremor, under the hypothesis that tremor is an oscillation of central origin commonly projected to all motor neurons that innervate a muscle. Our results show that under such conditions both paired discharges and enhanced motor neuron synchronization, two of the characteristic landmarks of tremor, emerge. Moreover, coherence and correlation analyses suggest that the central tremor oscillator is transmitted linearly by the motor neuron pool given that a small set (7 or 8) of motor neurons are sampled.