Adapted Beamforming: A Robust and Flexible Approach for Removing Various Types of Artifacts from TMS-EEG Data.

Electroencephalogram (EEG) recorded as response to transcranial magnetic stimulation (TMS) can be highly informative of cortical reactivity and connectivity. Reliable EEG interpretation requires artifact removal as the TMS-evoked EEG can contain high-amplitude artifacts. Several methods have been proposed to uncover clean neuronal EEG responses. In practice, determining which method to select for different types of artifacts is often difficult. Here, we used a unified data cleaning framework based on beamforming to improve the algorithm selection and adaptation to the recorded signals. Beamforming properties are well understood, so they can be used to yield customized methods for EEG cleaning based on prior knowledge of the artifacts and the data. The beamforming implementations also cover, but are not limited to, the popular TMS-EEG cleaning methods: independent component analysis (ICA), signal-space projection (SSP), signal-space-projection-source-informed-reconstruction method (SSP-SIR), the source-estimate-utilizing noise-discarding algorithm (SOUND), data-driven Wiener filter (DDWiener), and the multiple-source approach. In addition to these established methods, beamforming provides a flexible way to derive novel artifact suppression algorithms by considering the properties of the recorded data. With simulated and measured TMS-EEG data, we show how to adapt the beamforming-based cleaning to different data and artifact types, namely TMS-evoked muscle artifacts, ocular artifacts, TMS-related peripheral responses, and channel noise. Importantly, beamforming implementations are fast to execute: We demonstrate how the SOUND algorithm becomes orders of magnitudes faster via beamforming. Overall, the beamforming-based spatial filtering framework can greatly enhance the selection, adaptability, and speed of EEG artifact removal.

Targeting motor cortex high-excitability states defined by functional connectivity with real-time EEG-TMS.

We tested previous post-hoc findings indicating a relationship between functional connectivity (FC) in the motor network and corticospinal excitability (CsE), in a real-time EEG-TMS experiment in healthy participants. We hypothesized that high FC between left and right motor cortex predicts high CsE. FC was quantified in real-time by single-trial phase-locking value (stPLV), and TMS single pulses were delivered based on the current FC. CsE was indexed by motor-evoked potential (MEP) amplitude in a hand muscle. Possible confounding factors (pre-stimulus µ-power and phase, interstimulus interval) were evaluated post hoc. MEPs were significantly larger during high FC compared to low FC. Post hoc analysis revealed that the FC condition showed a significant interaction with µ-power in the stimulated hemisphere. Further, inter-stimulus interval (ISI) interacted with high vs. low FC conditions. In summary, FC was confirmed to be predictive of CsE, but should not be considered in isolation from µ-power and ISI. Moreover, FC was complementary to µ-phase in predicting CsE. Motor network FC is another marker of real-time accessible CsE beyond previously established markers, in particular phase and power of the µ rhythm, and may help define a more robust composite biomarker of high/low excitability states of human motor cortex.

Corticospinal excitability is highest at the early rising phase of sensorimotor µ-rhythm.

Alpha oscillations are thought to reflect alternating cortical states of excitation and inhibition. Studies of perceptual thresholds and evoked potentials have shown the scalp EEG negative phase of the oscillation to correspond to a short-lasting low-threshold and high-excitability state of underlying visual, somatosensory, and primary motor cortex. The negative peak of the oscillation is assumed to correspond to the state of highest excitability based on biophysical considerations and considerable effort has been made to improve the extraction of a predictive signal by individually optimizing EEG montages. Here, we investigate whether it is the negative peak of sensorimotor µ-rhythm that corresponds to the highest corticospinal excitability, and whether this is consistent between individuals. In 52 adult participants, a standard 5-channel surface Laplacian EEG montage was used to extract sensorimotor µ-rhythm during transcranial magnetic stimulation (TMS) of primary motor cortex. Post-hoc trials were sorted from 800 TMS-evoked motor potentials (MEPs) according to the pre-stimulus EEG (estimated instantaneous phase) and MEP amplitude (as an index of corticospinal excitability). Different preprocessing transformations designed to improve the accuracy by which µ-alpha phase predicts excitability were also tested. By fitting a sinusoid to the MEP amplitudes, sorted according to pre-stimulus EEG-phase, we found that excitability was highest during the early rising phase, at a significant delay with respect to the negative peak by on average 45° or 10 ms. The individual phase of highest excitability was consistent across study participants and unaffected by two different EEG-cleaning methods that utilize 64 channels to improve signal quality by compensating for individual noise level and channel covariance. Personalized transformations of the montage did not yield better prediction of excitability from µ-alpha phase. The relationship between instantaneous phase of a brain oscillation and fluctuating cortical excitability appears to be more complex than previously hypothesized. In TMS of motor cortex, a standard surface Laplacian 5-channel EEG montage is effective in extracting a predictive signal and the phase corresponding to the highest excitability appears to be consistent between individuals. This is an encouraging result with respect to the clinical potential of therapeutic personalized brain interventions in the motor system. However, it remains to be investigated, whether similar results can be obtained for other brain areas and brain oscillations targeted with EEG and TMS.

Brain-oscillation-synchronized stimulation to enhance motor recovery in early subacute stroke: a randomized controlled double-blind three- arm parallel-group exploratory trial comparing personalized, non- personalized and sham repetitive transcranial magnetic stimulation (Acronym: BOSS-STROKE).

BACKGROUND: Stroke is a major cause of death and the most frequent cause of permanent disability in western countries. Repetitive transcranial brain stimulation (rTMS) has been used to enhance neuronal plasticity after stroke, yet with only moderate effect sizes. Here we will apply a highly innovative technology that synchronizes rTMS to specific brain states identified by real-time analysis of electroencephalography. METHODS: One hundred forty-four patients with early subacute ischemic motor stroke will be included in a multicenter 3-arm parallel, randomized, double-blind, standard rTMS and sham rTMS-controlled exploratory trial in Germany. In the experimental condition, rTMS will be synchronized to the trough of the sensorimotor µ-oscillation, a high-excitability state, over ipsilesional motor cortex. In the standard rTMS control condition the identical protocol will be applied, but non-synchronized to the ongoing µ-oscillation. In the sham condition, the same µ-oscillation-synchronized protocol as in experimental condition will be applied, but with ineffective rTMS, using the sham side of an active/placebo TMS coil. The treatment will be performed over five consecutive work days (1,200 pulses per day, 6,000 pulses total). The primary endpoint will be motor performance after the last treatment session as measured by the Fugl-Meyer Assessment Upper Extremity. DISCUSSION: This study investigates, for the first time, the therapeutic efficacy of personalized, brain-state-dependent rTMS. We hypothesize that synchronization of rTMS with a high-excitability state will lead to significantly stronger improvement of paretic upper extremity motor function than standard or sham rTMS. Positive results may catalyze a paradigm-shift towards personalized brain-state-dependent stimulation therapies. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov (NCT05600374) on 10-21-2022.

Testing spasticity mechanisms in chronic stroke before and after intervention with contralesional motor cortex 1 Hz rTMS and physiotherapy.

BACKGROUND: Previous studies showed that repetitive transcranial magnetic stimulation (rTMS) reduces spasticity after stroke. However, clinical assessments like the modified Ashworth scale, cannot discriminate stretch reflex-mediated stiffness (spasticity) from passive stiffness components of resistance to muscle stretch. The mechanisms through which rTMS might influence spasticity are also not understood. METHODS: We measured the effects of contralesional motor cortex 1 Hz rTMS (1200 pulses + 50 min physiotherapy: 3×/week, for 4-6 weeks) on spasticity of the wrist flexor muscles in 54 chronic stroke patients using a hand-held dynamometer for objective quantification of the stretch reflex response. In addition, we measured the excitability of three spinal mechanisms thought to be related to post-stroke spasticity: post-activation depression, presynaptic inhibition and reciprocal inhibition before and after the intervention. Effects on motor impairment and function were also assessed using standardized stroke-specific clinical scales. RESULTS: The stretch reflex-mediated torque in the wrist flexors was significantly reduced after the intervention, while no change was detected in the passive stiffness. Additionally, there was a significant improvement in the clinical tests of motor impairment and function. There were no significant changes in the excitability of any of the measured spinal mechanisms. CONCLUSIONS: We demonstrated that contralesional motor cortex 1 Hz rTMS and physiotherapy can reduce the stretch reflex-mediated component of resistance to muscle stretch without affecting passive stiffness in chronic stroke. The specific physiological mechanisms driving this spasticity reduction remain unresolved, as no changes were observed in the excitability of the investigated spinal mechanisms.

Predicting motor behavior: an efficient EEG signal processing pipeline to detect brain states with potential therapeutic relevance for VR-based neurorehabilitation.

Virtual reality (VR)-based motor therapy is an emerging approach in neurorehabilitation. The combination of VR with electroencephalography (EEG) presents further opportunities to improve therapeutic efficacy by personalizing the paradigm. Specifically, the idea is to synchronize the choice and timing of stimuli in the perceived virtual world with fluctuating brain states relevant to motor behavior. Here, we present an open source EEG single-trial based classification pipeline that is designed to identify ongoing brain states predictive of the planning and execution of movements. 9 healthy volunteers each performed 1080 trials of a repetitive reaching task with an implicit two-alternative forced choice, i.e., use of the right or left hand, in response to the appearance of a visual target. The performance of the EEG decoding pipeline was assessed with respect to classification accuracy of right vs. left arm use, based on the EEG signal at the time of the stimulus. Different features, feature extraction methods, and classifiers were compared at different time windows; the number and location of informative EEG channels and the number of calibration trials needed were also quantified, as well as any benefits from individual-level optimization of pipeline parameters. This resulted in a set of recommended parameters that achieved an average 83.3% correct prediction on never-before-seen testing data, and a state-of-the-art 77.1% in a real-time simulation. Neurophysiological plausibility of the resulting classifiers was assessed by time-frequency and event-related potential analyses, as well as by Independent Component Analysis topographies and cortical source localization. We expect that this pipeline will facilitate the identification of relevant brain states as prospective therapeutic targets in closed-loop EEG-VR motor neurorehabilitation.

Recording brain responses to TMS of primary motor cortex by EEG - utility of an optimized sham procedure.

INTRODUCTION: Electroencephalography (EEG) is increasingly used to investigate brain responses to transcranial magnetic stimulation (TMS). A relevant issue is that TMS is associated with considerable auditory and somatosensory stimulation, causing peripherally evoked potentials (PEPs) in the EEG, which contaminate the direct cortical responses to TMS (TEPs). All previous attempts to control for PEPs suffer from significant limitations. OBJECTIVE/HYPOTHESIS: To design an optimized sham procedure to control all sensory input generated by subthreshold real TMS targeting the hand area of the primary motor cortex (M1), enabling reliable separation of TEPs from PEPs. METHODS: In 23 healthy (16 female) subjects, we recorded EEG activity evoked by an optimized sham TMS condition which masks and matches auditory and somatosensory co-stimulation during the real TMS condition: auditory control was achieved by noise masking and by using a second TMS coil that was placed on top of the real TMS coil and produced a calibrated sound pressure level. Somatosensory control was obtained by electric stimulation (ES) of the scalp with intensities sufficient to saturate somatosensory input. ES was applied in both the sham and real TMS conditions. Perception of auditory and somatosensory inputs in the sham and real TMS conditions were compared by psychophysical testing. Transcranially evoked EEG signal changes were identified by subtraction of EEG activity in the sham condition from EEG activity in the real TMS condition. RESULTS: Perception of auditory and somatosensory inputs in the sham vs. real TMS conditions was comparable. Both sham and real TMS evoked a series of similar EEG signal deflections and induced broadband power increase in oscillatory activity. Notably, the present procedure revealed EEG potentials and a transient increase in beta band power at the site of stimulation that were only present in the real TMS condition. DISCUSSION: The results validate the effectiveness of our optimized sham approach. Despite the presence of typical responses attributable to sensory input, the procedure provided evidence for direct cortical activation by subthreshold TMS of M1. The findings are relevant for future TMS-EEG experiments that aim at measuring regional brain target engagement controlled by an optimized sham procedure.

Artifacts in EEG-Based BCI Therapies: Friend or Foe?

EEG-based brain-computer interfaces (BCI) have promising therapeutic potential beyond traditional neurofeedback training, such as enabling personalized and optimized virtual reality (VR) neurorehabilitation paradigms where the timing and parameters of the visual experience is synchronized with specific brain states. While BCI algorithms are often designed to focus on whichever portion of a signal is most informative, in these brain-state-synchronized applications, it is of critical importance that the resulting decoder is sensitive to physiological brain activity representative of various mental states, and not to artifacts, such as those arising from naturalistic movements. In this study, we compare the relative classification accuracy with which different motor tasks can be decoded from both extracted brain activity and artifacts contained in the EEG signal. EEG data were collected from 17 chronic stroke patients while performing six different head, hand, and arm movements in a realistic VR-based neurorehabilitation paradigm. Results show that the artifactual component of the EEG signal is significantly more informative than brain activity with respect to classification accuracy. This finding is consistent across different feature extraction methods and classification pipelines. While informative brain signals can be recovered with suitable cleaning procedures, we recommend that features should not be designed solely to maximize classification accuracy, as this could select for remaining artifactual components. We also propose the use of machine learning approaches that are interpretable to verify that classification is driven by physiological brain states. In summary, whereas informative artifacts are a helpful friend in BCI-based communication applications, they can be a problematic foe in the estimation of physiological brain states.

Pulsed Facilitation of Corticospinal Excitability by the Sensorimotor µ-Alpha Rhythm.

Alpha oscillations (8-14 Hz) are assumed to gate information flow in the brain by means of pulsed inhibition; that is, the phasic suppression of cortical excitability and information processing once per alpha cycle, resulting in stronger net suppression for larger alpha amplitudes due to the assumed amplitude asymmetry of the oscillation. While there is evidence for this hypothesis regarding occipital alpha oscillations, it is less clear for the central sensorimotor µ-alpha rhythm. Probing corticospinal excitability via transcranial magnetic stimulation (TMS) of the primary motor cortex and the measurement of motor evoked potentials (MEPs), we have previously demonstrated that corticospinal excitability is modulated by both amplitude and phase of the sensorimotor µ-alpha rhythm. However, the direction of this modulation, its proposed asymmetry, and its underlying mechanisms remained unclear. We therefore used real-time EEG-triggered single- and paired-pulse TMS in healthy humans of both sexes to assess corticospinal excitability and GABA-A-receptor mediated short-latency intracortical inhibition (SICI) at rest during spontaneous high amplitude µ-alpha waves at different phase angles (peaks, troughs, rising and falling flanks) and compared them to periods of low amplitude (desynchronized) µ-alpha. MEP amplitude was facilitated during troughs and rising flanks, but no phasic suppression was observed at any time, nor any modulation of SICI. These results are best compatible with sensorimotor µ-alpha reflecting asymmetric pulsed facilitation but not pulsed inhibition of motor cortical excitability. The asymmetric excitability with respect to rising and falling flanks of the µ-alpha cycle further reveals that voltage differences alone cannot explain the impact of phase.SIGNIFICANCE STATEMENT The pulsed inhibition hypothesis, which assumes that alpha oscillations actively inhibit neuronal processing in a phasic manner, is highly influential and has substantially shaped our understanding of these oscillations. However, some of its basic assumptions, in particular its asymmetry and inhibitory nature, have rarely been tested directly. Here, we explicitly investigated the asymmetry of modulation and its direction for the human sensorimotor µ-alpha rhythm. We found clear evidence of pulsed facilitation, but not inhibition, in the human motor cortex, challenging the generalizability of the pulsed inhibition hypothesis and advising caution when interpreting sensorimotor µ-alpha changes in the sensorimotor system. This study also demonstrates how specific assumptions about the neurophysiological underpinnings of cortical oscillations can be experimentally tested noninvasively in humans.

The shaky ground truth of real-time phase estimation.

Instantaneous phase of brain oscillations in electroencephalography (EEG) is a measure of brain state that is relevant to neuronal processing and modulates evoked responses. However, determining phase at the time of a stimulus with standard signal processing methods is not possible due to the stimulus artifact masking the future part of the signal. Here, we quantify the degree to which signal-to-noise ratio and instantaneous amplitude of the signal affect the variance of phase estimation error and the precision with which "ground truth" phase is even defined, using both the variance of equivalent estimators and realistic simulated EEG data with known synthetic phase. Necessary experimental conditions are specified in which pre-stimulus phase estimation is meaningfully possible based on instantaneous amplitude and signal-to-noise ratio of the oscillation of interest. An open source toolbox is made available for causal (using pre-stimulus signal only) phase estimation along with a EEG dataset consisting of recordings from 140 participants and a best practices workflow for algorithm optimization and benchmarking. As an illustration, post-hoc sorting of open-loop transcranial magnetic stimulation (TMS) trials according to pre-stimulus sensorimotor µ-rhythm phase is performed to demonstrate modulation of corticospinal excitability, as indexed by the amplitude of motor evoked potentials.

Sensorimotor Oscillatory Phase-Power Interaction Gates Resting Human Corticospinal Output.

Oscillatory activity within sensorimotor networks is characterized by time-varying changes in phase and power. The influence of interactions between sensorimotor oscillatory phase and power on human motor function, like corticospinal output, is unknown. We addressed this gap in knowledge by delivering transcranial magnetic stimulation (TMS) to the human motor cortex during electroencephalography recordings in 20 healthy participants. Motor evoked potentials, a measure of corticospinal excitability, were categorized offline based on the mu (8-12 Hz) and beta (13-30 Hz) oscillatory phase and power at the time of TMS. Phase-dependency of corticospinal excitability was evaluated across a continuous range of power levels using trial-by-trial linear mixed-effects models. For mu, there was no effect of PHASE or POWER (P > 0.51), but a significant PHASE × POWER interaction (P = 0.002). The direction of phase-dependency reversed with changing mu power levels: corticospinal output was higher during mu troughs versus peaks when mu power was high while the opposite was true when mu power was low. A similar PHASE × POWER interaction was not present for beta oscillations (P > 0.11). We conclude that the interaction between sensorimotor oscillatory phase and power gates human corticospinal output to an extent unexplained by sensorimotor oscillatory phase or power alone.

Phase Synchronicity of µ-Rhythm Determines Efficacy of Interhemispheric Communication Between Human Motor Cortices.

The theory of communication through coherence predicts that effective connectivity between nodes in a distributed oscillating neuronal network depends on their instantaneous excitability state and phase synchronicity (Fries, 2005). Here, we tested this prediction by using state-dependent millisecond-resolved real-time electroencephalography-triggered dual-coil transcranial magnetic stimulation (EEG-TMS) (Zrenner et al., 2018) to target the EEG-negative (high-excitability state) versus EEG-positive peak (low-excitability state) of the sensorimotor µ-rhythm in the left (conditioning) and right (test) motor cortex (M1) of 16 healthy human subjects (9 female, 7 male). Effective connectivity was tested by short-interval interhemispheric inhibition (SIHI); that is, the inhibitory effect of the conditioning TMS pulse given 10-12 ms before the test pulse on the test motor-evoked potential. We compared the four possible combinations of excitability states (negative peak, positive peak) and phase relations (in-phase, out-of-phase) of the µ-rhythm in the conditioning and test M1 and a random phase condition. Strongest SIHI was found when the two M1 were in phase for the high-excitability state (negative peak of the µ-rhythm), whereas the weakest SIHI occurred when they were out of phase and the conditioning M1 was in the low-excitability state (positive peak). Phase synchronicity contributed significantly to SIHI variation, with stronger SIHI in the in-phase than out-of-phase conditions. These findings are in exact accord with the predictions of the theory of communication through coherence. They open a translational route for highly effective modification of brain connections by repetitive stimulation at instants in time when nodes in the network are phase synchronized and excitable.SIGNIFICANCE STATEMENT The theory of communication through coherence predicts that effective connectivity between nodes in distributed oscillating brain networks depends on their instantaneous excitability and phase relation. We tested this hypothesis in healthy human subjects by real-time analysis of brain states by electroencephalography in combination with transcranial magnetic stimulation of left and right motor cortex. We found that short-interval interhemispheric inhibition, a marker of interhemispheric effective connectivity, was maximally expressed when the two motor cortices were in phase for a high-excitability state (the trough of the sensorimotor µ-rhythm). We conclude that findings are consistent with the theory of communication through coherence. They open a translational route to highly effectively modify brain connections by repetitive stimulation at instants in time of phase-synchronized high-excitability states.

Phase of sensorimotor µ-oscillation modulates cortical responses to transcranial magnetic stimulation of the human motor cortex.

KEY POINTS: Oscillatory brain activity coordinates the response of cortical neurons to synaptic inputs in a phase-dependent manner. Larger motor-evoked responses are obtained in a hand muscle when transcranial magnetic stimulation (TMS) is synchronized to the phase of the sensorimotor µ-rhythm. In this study we further showed that TMS applied at the negative vs. positive peak of the µ-rhythm is associated with higher absolute amplitude of the evoked EEG potential at 100 ms after stimulation. This demonstrates that cortical responses are sensitive to excitability fluctuation with brain oscillations Our results indicate that brain state-dependent stimulation is a new useful technique for the investigation of stimulus-related cortical dynamics. ABSTRACT: Oscillatory brain activity coordinates the response of cortical neurons to synaptic inputs in a phase-dependent manner. Transcranial magnetic stimulation (TMS) of the human primary motor cortex elicits larger motor-evoked potentials (MEPs) when applied at the negative vs. positive peak of the sensorimotor µ-rhythm recorded with EEG, demonstrating that this phase represents a state of higher excitability of the cortico-spinal system. Here, we investigated the influence of the phase of the µ-rhythm on cortical responses to TMS as measured by EEG. We tested different stimulation intensities above and below resting motor threshold (RMT), and a realistic sham TMS condition. TMS at 110% RMT applied at the negative vs. positive peak of the µ-rhythm was associated with higher absolute amplitudes of TMS-evoked potentials at 70 ms (P70) and 100 ms (N100). Enhancement of the N100 was confirmed with negative peak-triggered 90% RMT TMS, while phase of the µ-rhythm did not influence evoked responses elicited by sham TMS. These findings extend the idea that TMS applied at the negative vs. positive peak of the endogenous µ-oscillation recruits a larger portion of neurons as a function of stimulation intensity. This further corroborates that brain oscillations determine fluctuations in cortical excitability and establishes phase-triggered EEG-TMS as a sensitive tool to investigate the effects of brain oscillations on stimulus-related cortical dynamics.

Closed-Loop Brain Stimulation.

In the same way that beauty lies in the eye of the beholder, what a stimulus does to the brain is determined not simply by the nature of the stimulus but by the nature of the brain that is receiving the stimulus at that instant in time. Over the past decades, therapeutic brain stimulation has typically applied open-loop fixed protocols and has largely ignored this principle. Only recent neurotechnological advancements have enabled us to predict the nature of the brain (i.e., the electrophysiological brain state in the next instance in time) with sufficient temporal precision in the range of milliseconds using feedforward algorithms applied to electroencephalography time-series data. This allows stimulation exclusively whenever the targeted brain area is in a prespecified excitability or connectivity state. Preclinical studies have shown that repetitive stimulation during a particular brain state (e.g., high-excitability state), but not during other states, results in lasting modification (e.g., long-term potentiation) of the stimulated circuits. Here, we survey the evidence that this is also possible at the systems level of the human cortex using electroencephalography-informed transcranial magnetic stimulation. We critically discuss opportunities and difficulties in developing brain state-dependent stimulation for more effective long-term modification of pathological brain networks (e.g., in major depressive disorder) than is achievable with conventional fixed protocols. The same real-time electroencephalography-informed transcranial magnetic stimulation technology will allow closing of the loop by recording the effects of stimulation. This information may enable stimulation protocol adaptation that maximizes treatment response. This way, brain states control brain stimulation, thereby introducing a paradigm shift from open-loop to closed-loop stimulation.

Blindly separated spontaneous network-level oscillations predict corticospinal excitability.

Objective.The corticospinal responses of the motor network to transcranial magnetic stimulation (TMS) are highly variable. While often regarded as noise, this variability provides a way of probing dynamic brain states related to excitability. We aimed to uncover spontaneously occurring cortical states that alter corticospinal excitability.Approach.Electroencephalography (EEG) recorded during TMS registers fast neural dynamics-unfortunately, at the cost of anatomical precision. We employed analytic Common Spatial Patterns technique to derive excitability-related cortical activity from pre-TMS EEG signals while overcoming spatial specificity issues.Main results.High corticospinal excitability was predicted by alpha-band activity, localized adjacent to the stimulated left motor cortex, and suggesting a travelling wave-like phenomenon towards frontal regions. Low excitability was predicted by alpha-band activity localized in the medial parietal-occipital and frontal cortical regions.Significance.We established a data-driven approach for uncovering network-level neural activity that modulates TMS effects. It requires no prior anatomical assumptions, while being physiologically interpretable, and can be employed in both exploratory investigation and brain state-dependent stimulation.

Brain state-dependent repetitive transcranial magnetic stimulation for motor stroke rehabilitation: a proof of concept randomized controlled trial.

Background: In healthy subjects, repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (M1) demonstrated plasticity effects contingent on electroencephalography (EEG)-derived excitability states, defined by the phase of the ongoing sensorimotor µ-oscillation. The therapeutic potential of brain state-dependent rTMS in the rehabilitation of upper limb motor impairment post-stroke remains unexplored. Objective: Proof-of-concept trial to assess the efficacy of rTMS, synchronized to the sensorimotor µ-oscillation, in improving motor impairment and reducing upper-limb spasticity in stroke patients. Methods: We conducted a parallel group, randomized double-blind controlled trial in 30 chronic stroke patients (clinical trial registration number: NCT05005780). The experimental intervention group received EEG-triggered rTMS of the ipsilesional M1 [1,200 pulses; 0.33 Hz; 100% of the resting motor threshold (RMT)], while the control group received low-frequency rTMS of the contralesional motor cortex (1,200 pulses; 1 Hz, 115% RMT), i.e., an established treatment protocol. Both groups received 12 rTMS sessions (20 min, 3× per week, 4 weeks) followed by 50 min of physiotherapy. The primary outcome measure was the change in upper-extremity Fugl-Meyer assessment (FMA-UE) scores between baseline, immediately post-treatment and 3 months' follow-up. Results: Both groups showed significant improvement in the primary outcome measure (FMA-UE) and the secondary outcome measures. This included the reduction in spasticity, measured objectively using the hand-held dynamometer, and enhanced motor function as measured by the Wolf Motor Function Test (WMFT). There were no significant differences between the groups in any of the outcome measures. Conclusion: The application of brain state-dependent rTMS for rehabilitation in chronic stroke patients is feasible. This pilot study demonstrated that the brain oscillation-synchronized rTMS protocol produced beneficial effects on motor impairment, motor function and spasticity that were comparable to those observed with an established therapeutic rTMS protocol. Clinical Trial Registration: ClinicalTrials.gov, identifier [NCT05005780].

A hybrid brain-muscle-machine interface for stroke rehabilitation: Usability and functionality validation in a 2-week intensive intervention.

Introduction: The primary constraint of non-invasive brain-machine interfaces (BMIs) in stroke rehabilitation lies in the poor spatial resolution of motor intention related neural activity capture. To address this limitation, hybrid brain-muscle-machine interfaces (hBMIs) have been suggested as superior alternatives. These hybrid interfaces incorporate supplementary input data from muscle signals to enhance the accuracy, smoothness and dexterity of rehabilitation device control. Nevertheless, determining the distribution of control between the brain and muscles is a complex task, particularly when applied to exoskeletons with multiple degrees of freedom (DoFs). Here we present a feasibility, usability and functionality study of a bio-inspired hybrid brain-muscle machine interface to continuously control an upper limb exoskeleton with 7 DoFs. Methods: The system implements a hierarchical control strategy that follows the biologically natural motor command pathway from the brain to the muscles. Additionally, it employs an innovative mirror myoelectric decoder, offering patients a reference model to assist them in relearning healthy muscle activation patterns during training. Furthermore, the multi-DoF exoskeleton enables the practice of coordinated arm and hand movements, which may facilitate the early use of the affected arm in daily life activities. In this pilot trial six chronic and severely paralyzed patients controlled the multi-DoF exoskeleton using their brain and muscle activity. The intervention consisted of 2 weeks of hBMI training of functional tasks with the system followed by physiotherapy. Patients' feedback was collected during and after the trial by means of several feedback questionnaires. Assessment sessions comprised clinical scales and neurophysiological measurements, conducted prior to, immediately following the intervention, and at a 2-week follow-up. Results: Patients' feedback indicates a great adoption of the technology and their confidence in its rehabilitation potential. Half of the patients showed improvements in their arm function and 83% improved their hand function. Furthermore, we found improved patterns of muscle activation as well as increased motor evoked potentials after the intervention. Discussion: This underscores the significant potential of bio-inspired interfaces that engage the entire nervous system, spanning from the brain to the muscles, for the rehabilitation of stroke patients, even those who are severely paralyzed and in the chronic phase.

Exploring Motor Network Connectivity in State-Dependent Transcranial Magnetic Stimulation: A Proof-of-Concept Study.

State-dependent non-invasive brain stimulation (NIBS) informed by electroencephalography (EEG) has contributed to the understanding of NIBS inter-subject and inter-session variability. While these approaches focus on local EEG characteristics, it is acknowledged that the brain exhibits an intrinsic long-range dynamic organization in networks. This proof-of-concept study explores whether EEG connectivity of the primary motor cortex (M1) in the pre-stimulation period aligns with the Motor Network (MN) and how the MN state affects responses to the transcranial magnetic stimulation (TMS) of M1. One thousand suprathreshold TMS pulses were delivered to the left M1 in eight subjects at rest, with simultaneous EEG. Motor-evoked potentials (MEPs) were measured from the right hand. The source space functional connectivity of the left M1 to the whole brain was assessed using the imaginary part of the phase locking value at the frequency of the sensorimotor µ-rhythm in a 1 s window before the pulse. Group-level connectivity revealed functional links between the left M1, left supplementary motor area, and right M1. Also, pulses delivered at high MN connectivity states result in a greater MEP amplitude compared to low connectivity states. At the single-subject level, this relation is more highly expressed in subjects that feature an overall high cortico-spinal excitability. In conclusion, this study paves the way for MN connectivity-based NIBS.

Repetitive sensorimotor mu-alpha phase-targeted afferent stimulation produces no phase-dependent plasticity related changes in somatosensory evoked potentials or sensory thresholds.

Phase-dependent plasticity has been proposed as a neurobiological mechanism by which oscillatory phase-amplitude cross-frequency coupling mediates memory process in the brain. Mimicking this mechanism, real-time EEG oscillatory phase-triggered transcranial magnetic stimulation (TMS) has successfully induced LTP-like changes in corticospinal excitability in the human motor cortex. Here we asked whether EEG phase-triggered afferent stimulation alone, if repetitively applied to the peaks, troughs, or random phases of the sensorimotor mu-alpha rhythm, would be sufficient to modulate the strength of thalamocortical synapses as assessed by changes in somatosensory evoked potential (SEP) N20 and P25 amplitudes and sensory thresholds (ST). Specifically, we applied 100 Hz triplets of peripheral electrical stimulation (PES) to the thumb, middle, and little finger of the right hand in pseudorandomized trials, with the afferent input from each finger repetitively and consistently arriving either during the cortical mu-alpha trough or peak or at random phases. No significant changes in SEP amplitudes or ST were observed across the phase-dependent PES intervention. We discuss potential limitations of the study and argue that suboptimal stimulation parameter choices rather than a general lack of phase-dependent plasticity in thalamocortical synapses are responsible for this null finding. Future studies should further explore the possibility of phase-dependent sensory stimulation.

Toward personalized circuit-based closed-loop brain-interventions in psychiatry: using symptom provocation to extract EEG-markers of brain circuit activity.

Symptom provocation is a well-established component of psychiatric research and therapy. It is hypothesized that specific activation of those brain circuits involved in the symptomatic expression of a brain pathology makes the relevant neural substrate accessible as a target for therapeutic interventions. For example, in the treatment of obsessive-compulsive disorder (OCD), symptom provocation is an important part of psychotherapy and is also performed prior to therapeutic brain stimulation with transcranial magnetic stimulation (TMS). Here, we discuss the potential of symptom provocation to isolate neurophysiological biomarkers reflecting the fluctuating activity of relevant brain networks with the goal of subsequently using these markers as targets to guide therapy. We put forward a general experimental framework based on the rapid switching between psychiatric symptom states. This enable neurophysiological measures to be derived from EEG and/or TMS-evoked EEG measures of brain activity during both states. By subtracting the data recorded during the baseline state from that recorded during the provoked state, the resulting contrast would ideally isolate the specific neural circuits differentially activated during the expression of symptoms. A similar approach enables the design of effective classifiers of brain activity from EEG data in Brain-Computer Interfaces (BCI). To obtain reliable contrast data, psychiatric state switching needs to be achieved multiple times during a continuous recording so that slow changes of brain activity affect both conditions equally. This is achieved easily for conditions that can be controlled intentionally, such as motor imagery, attention, or memory retention. With regard to psychiatric symptoms, an increase can often be provoked effectively relatively easily, however, it can be difficult to reliably and rapidly return to a baseline state. Here, we review different approaches to return from a provoked state to a baseline state and how these may be applied to different symptoms occurring in different psychiatric disorders.