Background: the use of combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) for the functional evaluation of the cerebral cortex in health and disease is becoming increasingly common. However, there is still some ambiguity regarding the extent to which brain responses to auditory and somatosensory stimulation contribute to the TMS-evoked potential (TEP). Objective/Hypothesis: to measure separately the contribution of auditory and somatosensory stimulation caused by TMS, and to assess their contribution to the TEP waveform, when stimulating the motor cortex (M1). Methods: 19 healthy volunteers underwent 7 blocks of EEG recording. To assess the impact of auditory stimulation on the TEP waveform, we used a standard figure of eight coil, with or without masking with a continuous noise reproducing the specific time-varying frequencies of the TMS click, stimulating at 90% of resting motor threshold. To further characterise auditory responses due to the TMS click, we used either a standard or a sham figure of eight coil placed on a pasteboard cylinder that rested on the scalp, with or without masking. Lastly, we used electrical stimulation of the scalp to investigate the possible contribution of somatosensory activation. Results: auditory stimulation induced a known pattern of responses in electrodes located around the vertex, which could be suppressed by appropriate noise masking. Electrical stimulation of the scalp alone only induced similar, non-specific scalp responses in the in the central electrodes. TMS, coupled with appropriate masking of sensory input, resulted in specific, lateralized responses at the stimulation site, lasting around 300 ms. Conclusions: if careful control of confounding sources is applied, TMS over M1 can generate genuine, lateralized EEG activity. By contrast, sensory evoked responses, if present, are represented by nonspecific, late (100e200 ms) components, located at the vertex, possibly due to saliency of the stimuli. Notably, the latter can confound the TEP if masking procedures are not properly used.

A rationale is provided for combining information from cortical rhythms and slow cortical potentials to detect the onsets of voluntary upper-limb movements. It is demonstrated that the two cortical processes supply complementary information that can be summed up to boost the performance of the detector. Successful results have been also obtained with stroke patients, which supports the use of the proposed system in brain-computer interface applications with this group of patients.

Continuous theta-burst stimulation (cTBS) is a repetitive transcranial magnetic stimulation paradigm reported to decrease the excitability of the stimulated cortical area and which is thought to reflect a form of inhibitory synaptic plasticity. However, since its introduction, the effect of cTBS has shown a remarkable variability in its effects, which are often quantified by measuring the amplitude of motor evoked potentials (MEPs). Part of this inconsistency in experimental results might be due to an intrinsic variability of TMS effects caused by genetic or neurophysiologic factors. However, it is also possible that MEP only reflect the excitability of a sub-population of output neurons; resting EEG power and measures combining TMS and electroencephalography (TMS-EEG) might represent a more thorough reflection of cortical excitability. The aim of the present study was to verify the robustness of several predictors of cTBS response, such as I wave recruitment and baseline MEP amplitude, and to test cTBS after-effects on multiple neurophysiologic measurements such as MEP, resting EEG power, local mean field power (LMFP), TMS-related spectral perturbation (TRSP), and inter-trial phase clustering (ITPC). As a result, we were not able to confirm either the expected decrease of MEP amplitude after cTBS or the ability of I wave recruitment and MEP amplitude to predict the response to cTBS. Resting EEG power, LMFP, TRSP, and ITPC showed a more consistent trend toward a decrease after cTBS. Overall, our data suggest that the effect of cTBS on corticospinal excitability is variable and difficult to predict with common electrophysiologic markers, while its effect might be clearer when probed with combined TMS and EEG.

Tremor in essential tremor (ET) is generated by pathological oscillations at 4-12 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 nine ET patients, with concurrent recordings of EEG activity. This analysis allowed us to infer 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. Furthermore, 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 pathological tremulous muscle activity.

Background: The association between motor-related cortical activity and peripheral stimulation with temporal precision has been proposed as a possible intervention to facilitate cortico-muscular pathways and thereby improve motor rehabilitation after stroke. Previous studies with patients have provided evidence of the possibility to implement brain-machine interface platforms able to decode motor intentions and use this information to trigger afferent stimulation and movement assistance. This study tests the use a low-latency movement intention detector to drive functional electrical stimulation assisting upper-limb reaching movements of patients with stroke.Methods: An eight-sessions intervention on the paretic arm was tested on four chronic stroke patients along 1 month. Patients' intentions to initiate reaching movements were decoded from electroencephalographic signals and used to trigger functional electrical stimulation that in turn assisted patients to do the task. The analysis of the patients' ability to interact with the intervention platform, the assessment of changes in patients' clinical scales and of the system usability and the kinematic analysis of the reaching movements before and after the intervention period were carried to study the potential impact of the intervention.Results: On average 66.3 ± 15.7% of trials (resting intervals followed by self-initiated movements) were correctly classified with the decoder of motor intentions. The average detection latency (with respect to the movement onsets estimated with gyroscopes) was 112 ± 278 ms. The Fügl-Meyer index upper extremity increased 11.5 ± 5.5 points with the intervention. The stroke impact scale also increased. In line with changes in clinical scales, kinematics of reaching movements showed a trend toward lower compensatory mechanisms. Patients' assessment of the therapy reflected their acceptance of the proposed intervention protocol.Conclusions: According to results obtained here with a small sample of patients, Brain-Machine Interfaces providing low-latency support to upper-limb reaching movements in patients with stroke are a reliable and usable solution for motor rehabilitation interventions with potential functional benefits.

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.

There is a growing interest in decomposing high-density surface electromyography (HDsEMG) into motor unit spike trains to improve knowledge on the neural control of muscle contraction.However, the reliability of decomposition approaches is sometimes questioned, especially because they require manual editing of the outputs. We aimed to assess the inter-operator reliability of the identification of motor unit spike trains. Eight operators with varying experience in HDsEMG decomposition were provided with the same data extracted using the convolutive kernel compensation method. They were asked to manually edit them following established procedures. Data included signals from three lower leg muscles and different submaximal intensities. After manual analysis, 126 ± 5 motor units were retained (range across operators: 119-134). A total of 3380 rate of agreement values were calculated (28 pairwise comparisons ´ 11 contractions/muscles ´ 4-28 motor units). The median rate of agreement value was 99.6%. Inter-operator reliability was excellent for both mean discharge rate and time at recruitment (intraclass correlation coefficient > 0.99). These results show that when provided with the same decomposed data and the same basic instructions, operators converge toward almost identical results. Our data have been made available so that they can be used for training new operators.

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.