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

In EEG and MEG studies on brain functional connectivity and source interactions can be performed at sensor or source level. Beamformers are well-established source-localization tools for MEG/EEG signals, being employed in source connectivity studies both in time and frequency domain. However, it has been demonstrated that beamformers suffer from a localization bias due to correlation between source time courses. This phenomenon has been ascertained by means of theoretical proofs and simulations. Nonetheless, the impact of correlated sources on localization outputs with real data has been disputed for a long time. In this paper, by means of a phantom, we address the correlation issue in a realistic MEG environment. Localization performances in the presence of simultaneously active sources are studied as a function of correlation degree and distance between sources. A linear constrained minimum variance (LCMV) beamformer is applied to the oscillating signals generated by the current dipoles within the phantom. Results show that high correlation affects mostly dipoles placed at small distances (1, 5 centimeters). In this case the sources merge. If the dipoles lie 3 centimeters apart, the beamformer localization detects attenuated power amplitudes and blurred sources as the correlation level raises.

Source activity correlation effects on LCMV beamformers in a realistic measurement environment.

Resting state functional connectivity of MEG data was studied in 29 children (9-10 years old). The weighted phase lag index (WPLI) was employed for estimating connectivity and compared to coherence. To further evaluate the network structure, a graph analysis based on WPLI was used to determine clustering coefficient (C) and betweenness centrality (BC) as local coefficients as well as the characteristic path length (L) as a parameter for global interconnectedness. The network's modular structure was also calculated to estimate functional segregation. A seed region was identified in the central occipital area based on the power distribution at the sensor level in the alpha band. WPLI reveals a specific connectivity map different from power and coherence. BC and modularity show a strong level of connectedness in the occipital area between lateral and central sensors. C shows different isolated areas of occipital sensors. Globally, a network with the shortest L is detected in the alpha band, consistently with the local results. Our results are in agreement with findings in adults, indicating a similar functional network in children at this age in the alpha band. The integrated use of WPLI and graph analysis can help to gain a better description of resting state networks.

Weighted phase lag index and graph analysis: preliminary investigation of functional connectivity during resting state in children.

Electro- and magnetoencephalography allow for non-invasive investigation of human brain activation and corresponding networks with high temporal resolution. Still, no correct network detection is possible without reliable source localization. In this paper, we examine four different source localization schemes under a common Variational Bayesian framework. A Bayesian approach to the Minimum Norm Model (MNM), an Empirical Bayesian Beamformer (EBB) and two iterative Bayesian schemes (Automatic Relevance Determination (ARD) and Greedy Search (GS)) are quantitatively compared. While EBB and MNM each use a single empirical prior, ARD and GS employ a library of anatomical priors that define possible source configurations. The localization performance was investigated as a function of (i) the number of sources (one vs. two vs. three), (ii) the signal to noise ratio (SNR; 5 levels) and (iii) the temporal correlation of source time courses (for the cases of two or three sources). We also tested whether the use of additional bilateral priors specifying source covariance for ARD and GS algorithms improved performance. Our results show that MNM proves effective only with single source configurations. EBB shows a spatial accuracy of few millimeters with high SNRs and low correlation between sources. In contrast, ARD and GS are more robust to noise and less affected by temporal correlations between sources. However, the spatial accuracy of ARD and GS is generally limited to the order of one centimeter. We found that the use of correlated covariance priors made no difference to ARD/GS performance.

Source reconstruction accuracy of MEG and EEG Bayesian inversion approaches.

Electro - et magn&eacute;toenc&eacute;phalographie permet une enqu&ecirc;te non invasive de l&#39;homme du cerveau activation et r&eacute;seaux correspondants avec une haute r&eacute;solution temporelle. Pourtant, aucune d&eacute;tection de r&eacute;seau correct n&#39;est possible sans localisation des sources fiables. Dans cet article, nous examinons quatre sch&eacute;mas de localisation de source diff&eacute;rente dans un cadre commun de bay&eacute;sienne variationnelle. Une approche bay&eacute;sienne pour le mod&egrave;le de norme Minimum (MNM), un faisceau de bay&eacute;sienne empirique (CA&Eacute;) et deux r&eacute;gimes de bay&eacute;sien it&eacute;ratifs (d&eacute;termination automatique de pertinence (ARD) et avide recherche (GS)) sont compar&eacute;es quantitativement. EBB et MNM chaque utilisent un seul avant empirique, ARD et GS emploient une biblioth&egrave;que des lois a priori anatomiques qui d&eacute;finissent les configurations de source possible. La performance de localisation a &eacute;t&eacute; &eacute;tudi&eacute;e en fonction de (i) le nombre de sources (une vs deux vs. trois), (ii) le rapport signal sur bruit (SNR; 5 niveaux) et (iii) la corr&eacute;lation temporelle des cours temps source (pour les cas de deux ou trois sources). Aussi, nous avons v&eacute;rifi&eacute; si l&#39;utilisation d&#39;autres prieurs bilat&eacute;raux sp&eacute;cifiant la covariance de la source pour les algorithmes ARD et GS performances am&eacute;lior&eacute;es. Nos r&eacute;sultats montrent que les MNM s&#39;av&egrave;re efficace uniquement avec des configurations de source unique. EBB montre une pr&eacute;cision spatiale de quelques millim&egrave;tres avec le SNRs &eacute;lev&eacute;s et faible corr&eacute;lation entre les sources. En revanche, ARD et GS sont plus robustes au bruit et moins affect&eacute;e par des corr&eacute;lations temporelles entre les sources. Cependant, la pr&eacute;cision spatiale d&#39;ARD et GS est g&eacute;n&eacute;ralement limit&eacute;e &agrave; l&#39;ordre d&#39;un centim&egrave;tre. Nous avons trouv&eacute; que l&#39;utilisation des lois a priori de covariance corr&eacute;lation ne faisait aucune diff&eacute;rence de performance de l&#39;ARD/GS.

Approches de pr&eacute;cision reconstruction source de MEG et EEG bay&eacute;sienne d&#39;inversion.

Electro - e magnetoencefalografia consentono di indagine non invasiva di umani corrispondenti reti con alta risoluzione temporale e attivazione del cervello. Ancora, nessun rilevamento di rete corretto &egrave; possibile senza localizzazione fonte affidabile. In questa carta, esaminiamo quattro schemi di localizzazione diversa fonte sotto un quadro comune di Bayesian variazionale. Un approccio bayesiano per il modello di norma minimo (MNM), un Beamformer di bayesiana empirica (EBB) e due schemi di Bayesian iterativi (determinazione automatica di pertinenza (ARD) e avida ricerca (GS)) sono quantitativamente rispetto. Mentre EBB e MNM ogni utilizza un singolo prima empirico, ARD e GS impiegano una libreria di priori anatomiche che definire fonte di possibili configurazioni. Le prestazioni di localizzazione &egrave; stata studiata in funzione di (i) il numero di fonti (uno contro due vs tre), (ii) il segnale-rumore (SNR; 5 livelli) e (iii) la correlazione temporale dei corsi tempo fonte (per i casi di due o tre fonti). Abbiamo testato anche se l&#39;uso di ulteriori priori bilaterali specificando covarianza fonte per gli algoritmi di ARD e GS migliorato le prestazioni. I nostri risultati mostrano che gli MNM si rivela efficaci solo con configurazioni di singola origine. EBB Mostra una precisione spaziale di pochi millimetri con SNRs ad alta e bassa correlazione tra fonti. Al contrario, ARD e GS sono pi&ugrave; robusti di rumore e meno influenzato da correlazioni temporali tra le fonti. Tuttavia, la precisione spaziale di ARD e GS &egrave; generalmente limitata all&#39;ordine di un centimetro. Abbiamo trovato che l&#39;uso dei priori covarianza correlato non fatto alcuna differenza per le prestazioni di ARD/GS.

Precisione ricostruzione fonte di MEG ed EEG Bayesian inversione si avvicina.

In everyday life, our auditory system is bombarded with many signals in complex auditory scenes. Limited processing capacities allow only a fraction of these signals to enter perceptual awareness. This magnetoencephalography (MEG) study used informational masking to identify the neural mechanisms that enable auditory awareness. On each trial, participants indicated whether they detected a pair of sequentially presented tones (i.e., the target) that were embedded within a multi-tone background. We analysed MEG activity for 'hits' and 'misses', separately for the first and second tones within a target pair. Comparing physically identical stimuli that were detected or missed provided insights into the neural processes underlying auditory awareness. While the first tone within a target elicited a stronger early P50m on hit trials, only the second tone evoked a negativity at 150 ms, which may index segregation of the tone pair from the multi-tone background. Notably, a later sustained deflection peaking around 300 and 500 ms (P300m) was the only component that was significantly amplified for both tones, when they were detected pointing towards its key role in perceptual awareness. Additional Dynamic Causal Modelling analyses indicated that the negativity at 150 ms underlying auditory stream segregation is mediated predominantly via changes in intrinsic connectivity within auditory cortices. By contrast, the later P300m response as a signature of perceptual awareness relies on interactions between parietal and auditory cortices. In conclusion, our results suggest that successful detection and hence auditory awareness of a two-tone pair within complex auditory scenes relies on recurrent processing between auditory and higher-order parietal cortices.

Detecting tones in complex auditory scenes.

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.

Alpha-5 gamma-aminobutyric acid type A receptors (α5-GABAARs) are located extrasynaptically, regulate neuronal excitability through tonic inhibition, and are fundamentally important for processes such as plasticity and learning. For example, pharmacological blockade of α5-GABAAR in mice with ischemic stroke improved recovery of function by normalizing exaggerated perilesional α5-GABAAR-dependent tonic inhibition. S44819 is a novel competitive selective antagonist of the α5-GABAAR at the GABA-binding site. Pharmacological modulation of α5-GABAAR-mediated tonic inhibition has never been investigated in the human brain. Here, we used transcranial magnetic stimulation (TMS) to test the effects of a single oral dose of 50 and 100 mg of S44819 on electromyographic (EMG) and electroencephalographic (EEG) measures of cortical excitability in 18 healthy young adults in a randomized, double-blinded, placebo-controlled, crossover phase I study. A dose of 100 mg, but not 50 mg, of S44819 decreased active motor threshold, the intensity needed to produce a motor evoked potential of 0.5 mV, and the amplitude of the N45, a GABAAergic component of the TMS-evoked EEG response. The peak serum concentration of 100 mg S44819 correlated directly with the decrease in N45 amplitude. Short-interval intracortical inhibition, a TMS-EMG measure of synaptic GABAAergic inhibition, and other components of the TMS-evoked EEG response remained unaffected. These findings provide first time evidence that the specific α5-GABAAR antagonist S44819 reached human cortex to impose an increase in cortical excitability. These data warrant further development of S44819 in a human clinical trial to test its efficacy in enhancing recovery of function after ischemic stroke.

Effects of the Selective α5-GABAAR Antagonist S44819 on Excitability in the Human Brain: A TMS-EMG and TMS-EEG Phase I Study.

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.

The pre-supplementary motor area (pre-SMA) is engaged in speech comprehension under difficult circumstances such as poor acoustic signal quality or time-critical conditions. Previous studies found that left pre-SMA is activated when subjects listen to accelerated speech. Here, the functional role of pre-SMA was tested for accelerated speech comprehension by inducing a transient "virtual lesion" using continuous theta-burst stimulation (cTBS). Participants were tested (1) prior to (pre-baseline), (2) 10 min after (test condition for the cTBS effect), and (3) 60 min after stimulation (post-baseline) using a sentence repetition task (formant-synthesized at rates of 8, 10, 12, 14, and 16 syllables/s). Speech comprehension was quantified by the percentage of correctly reproduced speech material. For high speech rates, subjects showed decreased performance after cTBS of pre-SMA. Regarding the error pattern, the number of incorrect words without any semantic or phonological similarity to the target context increased, while related words decreased. Thus, the transient impairment of pre-SMA seems to affect its inhibitory function that normally eliminates erroneous speech material prior to speaking or, in case of perception, prior to encoding into a semantically/pragmatically meaningful message.

Reduced Performance During a Sentence Repetition Task by Continuous Theta-Burst Magnetic Stimulation of the Pre-supplementary Motor Area.

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.

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
Source activity correlation effects on LCMV beamformers in a realistic measurement environment. Computational and mathematical methods in medicine\| PubMed ID: 22611439	2012
Weighted phase lag index and graph analysis: preliminary investigation of functional connectivity during resting state in children. Computational and mathematical methods in medicine\| PubMed ID: 23049617	2012
Source reconstruction accuracy of MEG and EEG Bayesian inversion approaches. PloS one\| PubMed ID: 23284840	2012
Detecting tones in complex auditory scenes. NeuroImage\| PubMed ID: 26244276	2015
Closed-Loop Neuroscience and Non-Invasive Brain Stimulation: A Tale of Two Loops. Frontiers in cellular neuroscience\| PubMed ID: 27092055	2016
Effects of the Selective α5-GABAAR Antagonist S44819 on Excitability in the Human Brain: A TMS-EMG and TMS-EEG Phase I Study. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 27927951	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
Reduced Performance During a Sentence Repetition Task by Continuous Theta-Burst Magnetic Stimulation of the Pre-supplementary Motor Area. Frontiers in neuroscience\| PubMed ID: 29896086	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
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

Paolo Belardinelli

Biography

JoVE Journal Publications

Other Publications