brain-state-dependent-brain-stimulation-with-real-time

Brain State-dependent Brain Stimulation with Real-time Electroencephalography-Triggered Transcranial Magnetic Stimulation

The effect of a stimulus to the brain depends not only on the parameters of the stimulus but also on the dynamics of brain activity at the time of the ...

University of Tübingen

Closed-loop neuroscience is receiving increasing attention with recent technological advances that enable complex feedback loops to be implemented with millisecond resolution on commodity hardware. We summarize emerging conceptual and methodological frameworks that are available to experimenters investigating a "brain in the loop" using non-invasive brain stimulation and briefly review the experimental and therapeutic implications. We take the view that closed-loop neuroscience in fact deals with two conceptually quite different loops: a "brain-state dynamics" loop, used to couple with and modulate the trajectory of neuronal activity patterns, and a "task dynamics" loop, that is the bidirectional motor-sensory interaction between brain and (simulated) environment, and which enables goal-directed behavioral tasks to be incorporated. Both loops need to be considered and combined to realize the full experimental and therapeutic potential of closed-loop neuroscience. 

Closed-Loop Neuroscience and Non-Invasive Brain Stimulation: A Tale of Two Loops.

Mutations in STX1B encoding the presynaptic protein syntaxin-1B are associated with febrile seizures with or without epilepsy. It is unclear to what extent these mutations are linked to abnormalities of cortical glutamatergic or GABAergic neurotransmission. We explored this question using single- and paired-pulse transcranial magnetic stimulation (TMS) excitability markers.

Motor cortex excitability in seizure-free STX1B mutation carriers with a history of epilepsy and febrile seizures.

Rapidly changing excitability states in an oscillating neuronal network can explain response variability to external stimulation, but if repetitive stimulation of always the same high- or low-excitability state results in long-term plasticity of opposite direction has never been explored in vivo.

Real-time EEG-defined excitability states determine efficacy of TMS-induced plasticity in human motor cortex.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique with potential for cost-effective therapeutic neuromodulation. Although positive therapeutic effects were found by stimulating the dorsolateral prefrontal cortex (DLPFC), few studies have investigated physiological effects of DLPFC-tDCS.

Modulation of cortical responses by transcranial direct current stimulation of dorsolateral prefrontal cortex: A resting-state EEG and TMS-EEG study.

The analysis of cortical responses to transcranial magnetic stimulation (TMS) recorded by electroencephalography (EEG) has been successfully applied to study human cortical physiology. However, in addition to the (desired) activation of cortical neurons and fibers, TMS also causes (undesired) indirect brain responses through auditory and somatosensory stimulation, which may contribute significantly to the overall EEG signal and mask the effects of intervention on direct cortical responses.

Comparison of cortical EEG responses to realistic sham versus real TMS of human motor cortex.

Corticospinal excitability depends on the current brain state. The recent development of real-time EEG-triggered transcranial magnetic stimulation (EEG-TMS) allows studying this relationship in a causal fashion. Specifically, it has been shown that corticospinal excitability is higher during the scalp surface negative EEG peak compared to the positive peak of μ-oscillations in sensorimotor cortex, as indexed by larger motor evoked potentials (MEPs) for fixed stimulation intensity.

EEG-triggered TMS reveals stronger brain state-dependent modulation of motor evoked potentials at weaker stimulation intensities.

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.

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

Repetitive transcranial magnetic stimulation (rTMS) can induce excitability changes of a stimulated brain area through synaptic plasticity mechanisms. High-frequency (100 Hz) triplets of rTMS synchronized to the negative but not the positive peak of the ongoing sensorimotor μ-rhythm isolated with the concurrently acquired electroencephalography (EEG) resulted in a reproducible long-term potentiation like increase of motor evoked potential (MEP) amplitude, an index of corticospinal excitability (Zrenner et al. 2018, Brain Stimul 11:374-389). Here, we analyzed the EEG and TMS-EEG data from (Zrenner et al., 2018) to investigate the effects of μ-rhythm-phase-dependent burst-rTMS on EEG-based measures of cortical excitability. We used resting-state EEG to assess μ- and β-power in the motor cortex ipsi- and contralateral to the stimulation, and single-pulse TMS-evoked and induced EEG responses in the stimulated motor cortex. We found that μ-rhythm-phase-dependent burst-rTMS did not significantly change any of these EEG measures, despite the presence of a significant differential and reproducible effect on MEP amplitude. We conclude that EEG measures of cortical excitability do not reflect corticospinal excitability as measured by MEP amplitude. Most likely this is explained by the fact that rTMS induces complex changes at the molecular and synaptic level towards both excitation and inhibition that cannot be differentiated at the macroscopic level by EEG.

Nil effects of μ-rhythm phase-dependent burst-rTMS on cortical excitability in humans: A resting-state EEG and TMS-EEG study.

Ongoing brain activity has been implicated in the modulation of cortical excitability. The combination of electroencephalography (EEG) and transcranial magnetic stimulation (TMS) in a real-time triggered setup is a novel method for testing hypotheses about the relationship between spontaneous neuronal oscillations, cortical excitability, and synaptic plasticity. For this method, a reliable real-time extraction of the neuronal signal of interest from scalp EEG with high signal-to-noise ratio (SNR) is of crucial importance. Here we compare individually tailored spatial filters as computed by spatial-spectral decomposition (SSD), which maximizes SNR in a frequency band of interest, against established local C3-centered Laplacian filters for the extraction of the sensorimotor μ-rhythm. Single-pulse TMS over the left primary motor cortex was synchronized with the surface positive or negative peak of the respective extracted signal, and motor evoked potentials (MEP) were recorded with electromyography (EMG) of a contralateral hand muscle. Both extraction methods led to a comparable degree of MEP amplitude modulation by phase of the sensorimotor μ-rhythm at the time of stimulation. This could be relevant for targeting other brain regions with no working benchmark such as the local C3-centered Laplacian filter, as sufficient SNR is an important prerequisite for reliable real-time single-trial detection of EEG features.

Article	Year
Closed-Loop Neuroscience and Non-Invasive Brain Stimulation: A Tale of Two Loops. Frontiers in cellular neuroscience\| PubMed ID: 27092055	2016
Motor cortex excitability in seizure-free STX1B mutation carriers with a history of epilepsy and febrile seizures. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology\| PubMed ID: 29101845	2017
Real-time EEG-defined excitability states determine efficacy of TMS-induced plasticity in human motor cortex. Brain stimulation\| PubMed ID: 29191438	2018
Modulation of cortical responses by transcranial direct current stimulation of dorsolateral prefrontal cortex: A resting-state EEG and TMS-EEG study. Brain stimulation\| PubMed ID: 29921529	2018
Comparison of cortical EEG responses to realistic sham versus real TMS of human motor cortex. Brain stimulation\| PubMed ID: 30143417	2018
EEG-triggered TMS reveals stronger brain state-dependent modulation of motor evoked potentials at weaker stimulation intensities. Brain stimulation\| PubMed ID: 30268710	2019
Sensorimotor Oscillatory Phase-Power Interaction Gates Resting Human Corticospinal Output. Cerebral cortex (New York, N.Y. : 1991)\| PubMed ID: 30496352	2018
Nil effects of μ-rhythm phase-dependent burst-rTMS on cortical excitability in humans: A resting-state EEG and TMS-EEG study. PloS one\| PubMed ID: 30532205	2018
μ-Rhythm Extracted With Personalized EEG Filters Correlates With Corticospinal Excitability in Real-Time Phase-Triggered EEG-TMS. Frontiers in neuroscience\| PubMed ID: 30618580	2018
Reproducibility in TMS-EEG studies: A call for data sharing, standard procedures and effective experimental control. Brain stimulation\| PubMed ID: 30738777	2019

Christoph Zrenner

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