Manipulating neuronal communication by using low-intensity repetitive transcranial magnetic stimulation combined with electroencephalogram

Repetitive transcranial magnetic stimulation (rTMS) modulates ongoing brain rhythms by activating neuronal structures and evolving different neuronal mechanisms. In the current work, the role of stimulation strength and frequency for brain rhythms was studied. We hypothesized that a weak oscillating electric field induced by low-intensity rTMS could induce entrainment effects in the brain. To test the hypothesis, we conducted three separate experiments, in which we stimulated healthy human participants with rTMS. We individualized stimulation parameters using computational modeling of induced electric fields in the targets and individual frequency estimated by electroencephalography (EEG). We demonstrated the immediately induced entrainment of occipito-parietal and sensorimotor mu-alpha rhythm by low-intensity rTMS that resulted in phase and amplitude changes measured by EEG. Additionally, we found long-lasting corticospinal excitability changes in the motor cortex measured by motor evoked potentials from the corresponding musle.2021-11-2

Properties of transcranial electric stimulation artifacts in EEG and MEG recordings

Transcranial electrical stimulation (tES) is a non-invasive neuromodulation technique applicable to healthy and diseased subjects that can manipulate brain activity for both therapeutic and research purposes. Simultaneous combination of tES with non-invasive brain imaging techniques might be useful for guiding stimulation parameters to influence brain activity efficiently, and for closed-loop stimulation of the brain. Moreover, such a simultaneous observation is necessary to understand mechanisms underlying tES effects at the network level. However, strong stimulation artifacts at the stimulation frequency make such a simultaneous monitoring by means of MEG or EEG (M/EEG) challenging. At commonly used tES strengths, these artifacts are about 1000 times bigger than brain signals recorded by M/EEG. Therefore, sub-optimal removal of stimulation artifacts leads to residual artifacts that could be mistakenly taken as brain signals. Designing optimal artifact-removal methods requires detailed knowledge about properties of artifacts. In this dissertation, we provide this missing fundamental information by carefully analyzing M/EEG signals during tES. We show that, in contrast to previous assumptions, tES artifacts are non-linearly transformed versions of stimulation currents. This non-linearity manifests itself in both the amplitude and the phase of tES artifacts, and is partly dependent on the stimulation frequency. Specifically, we show that each heartbeat and every respiratory breath strongly modulates both the amplitude and the phase of stimulation artifacts, which makes artifacts dependent on the physiological state of the subject. Due to these modulations, tES artifacts are not narrow band, but contaminate recorded signals even 8 Hz beyond the stimulation frequency. Moreover, the spatial pattern of artifacts continuously varies over time, which decreases the performance of artifact-removal methods based on PCA, ICA or beamforming. In light of our findings, we evaluate available artifact-removal pipelines and show that their outputs are contaminated with residual artifacts, which could have potentially driven biological conclusions made using these pipelines. Finally, we discuss consequences of our findings and provide some ideas for future research regarding how to investigate brain activity during tES. In sum, this dissertation reconsiders assumptions regarding tES artifacts in M/EEG and provides missing fundamental information about their properties. Our results could be used to prevent pitfalls of simultaneous tES and M/EEG and to design and evaluate new artifact-removal pipelines

TMS-evoked long-lasting artefacts: A new adaptive algorithm for EEG signal correction

OBJECTIVE: During EEG the discharge of TMS generates a long-lasting decay artefact (DA) that makes the analysis of TMS-evoked potentials (TEPs) difficult. Our aim was twofold: (1) to describe how the DA affects the recorded EEG and (2) to develop a new adaptive detrend algorithm (ADA) able to correct the DA. METHODS: We performed two experiments testing 50 healthy volunteers. In experiment 1, we tested the efficacy of ADA by comparing it with two commonly-used independent component analysis (ICA) algorithms. In experiment 2, we further investigated the efficiency of ADA and the impact of the DA evoked from TMS over frontal, motor and parietal areas. RESULTS: Our results demonstrated that (1) the DA affected the EEG signal in the spatiotemporal domain; (2) ADA was able to completely remove the DA without affecting the TEP waveforms; (3). ICA corrections produced significant changes in peak-to-peak TEP amplitude. CONCLUSIONS: ADA is a reliable solution for the DA correction, especially considering that (1) it does not affect physiological responses; (2) it is completely data-driven and (3) its effectiveness does not depend on the characteristics of the artefact and on the number of recording electrodes. SIGNIFICANCE: We proposed a new reliable algorithm of correction for long-lasting TMS-EEG artifacts

Disruption and rescue of interareal theta phase coupling and adaptive behavior

Rescuing executive functions in people with neurological and neuropsychiatric disorders has been a major goal of psychology and neuroscience for decades. Innovative computer-training regimes for executive functions have made tremendous inroads, yet the positive effects of training have not always translated into improved cognitive functioning and often take many days to emerge. In the present study, we asked whether it was possible to immediately change components of executive function by directly manipulating neural activity using a stimulation technology called high-definition transcranial alternating current stimulation (HD-tACS). Twenty minutes of inphase stimulation over medial frontal cortex (MFC) and right lateral prefrontal cortex (lPFC) synchronized theta (∼6 Hz) rhythms between these regions in a frequency and spatially specific manner and rapidly improved adaptive behavior with effects lasting longer than 40 min. In contrast, antiphase stimulation in the same individuals desynchronized MFC-lPFC theta phase coupling and impaired adaptive behavior. Surprisingly, the exogenously driven impairments in performance could be instantly rescued by reversing the phase angle of alternating current. The results suggest executive functions can be rapidly up- or down-regulated by modulating theta phase coupling of distant frontal cortical areas and can contribute to the development of tools for potentially normalizing executive dysfunction in patient populations.Published versio

Closed-loop approaches for innovative neuroprostheses

The goal of this thesis is to study new ways to interact with the nervous system in case of damage or pathology. In particular, I focused my effort towards the development of innovative, closed-loop stimulation protocols in various scenarios: in vitro, ex vivo, in vivo

Assessment of whole-head magnetoencephalography during transcranial electric entrainment of brain oscillations

Application of non-invasive brain stimulation for perturbing brain activity is well established. Various forms of brain stimulation protocols have been effectively demonstrated to modulate behavior associated with the perturbed brain activity. However, the interaction of brain stimulation with ongoing brain activity has been challenging to characterize as the stimulation artifacts in the recordings of brain activity impedes such characterization. The proposed amplitude modulated transcranial alternating current stimulation (tACSAM) attenuates possible stimulation artifacts at the frequency of interest. This is possible by modulating the amplitude of high frequency transcranial alternating current (tACS) signal at a lower physiological frequency of interest to generate the tACSAM signal. Furthermore, application of tACSAM allows localization of the perturbed brain activity with millimeter precision by applying spatial filters on magnetoencephalography (MEG) recordings. For characterization of the tACSAM-perturbed brain activity, conventional spectral analysis may not be sufficient. Thus, power and PLV were compared between tACS and tACSAM in a phantom model and MEG data recorded from healthy human volunteers. The synchronization estimate, phase lock value (PLV), is a measure of circular variance between two signals calculated as a function of instantaneous phase difference between the ongoing brain activity and the applied stimulation signal. Even though, systematic linear phase shifts due to the applied tES signal occur in MEG sensors, mathematically such systematic linear phase shifts nullify while calculating PLV. Systematic evaluation of the MEG data acquired during tACSAM showed increased PLV compared to tACS indicating increased demodulation in such paradigm. Upon observing tACSAM-related increased demodulation, it was still unclear whether such perturbations of brain activity could modulate behavior. To address this question, twenty volunteers while engaging in a working memory paradigm received tACSAM or no stimulation. Working memory is associated with transient storage and processing of information. Increasing the difficulty of working memory paradigm increases the amplitude of brain activity in the theta band (4 – 8 Hz), while encoding the temporal order of the transient information in the phase of the theta activity. Thus, by targeting individual’s theta peak frequency using tACSAM, it was possible to modulate the accuracy in the working memory paradigm. The accuracy on a working memory parading of volunteers receiving tACSAM deteriorated compared to the participants who did not receive brain stimulation. Therefore, targeting brain activity in theta band using tACSAM interferes with execution of normal working memory processes, probably by interfering with the maintenance of temporal order of the transient information. Furthermore, tACSAM but not sham stimulation inhibited the increase in amplitude of theta activity during the n-back task, which is essential for working memory processes. Even though, it is possible to assess the brain activity recorded during tACSAM, presence of stimulation artifacts in the assessed brain activity cannot be excluded. However, it was possible to gather evidence that tACSAM is associated with demodulation. TACSAM-induced phase synchrony at the modulation frequency was larger compared to tACS even though the power during tACS is larger compared to tACSAM. This observation is in favor of possible functional interaction of tACSAM signal with neurons in the brain. However, currently it is not possible to distinguish between the contribution towards demodulation of tACSAM signal by non-linearities of the stimulation setup and functional interactions with neurons in the brain. In conclusion, tACSAM can alter cognitive function, such as working memory performance, possibly through entrainment. The results obtained from such investigations must be interpreted with great care, as the extent by which possible stimulation artifacts impact the MEG recordings is not entirely clear. Further investigations are necessary to develop quantitative assessment techniques for characterizing artifacts of the stimulation and eventually develop brain state dependent stimulation paradigms in real time as a research tool and therapeutic intervention

Transcranial Electric Stimulation Entrains Cortical Neuronal Populations in Rats

Low intensity electric fields have been suggested to affect the ongoing neuronal activity in vitro and in human studies. However, the physiological mechanism of how weak electrical fields affect and interact with intact brain activity is not well understood. We performed in vivo extracellular and intracellular recordings from the neocortex and hippocampus of anesthetized rats and extracellular recordings in behaving rats. Electric fields were generated by sinusoid patterns at slow frequency (0.8, 1.25 or 1.7 Hz) via electrodes placed on the surface of the skull or the dura. Transcranial electric stimulation (TES) reliably entrained neurons in widespread cortical areas, including the hippocampus. The percentage of TES phase-locked neurons increased with stimulus intensity and depended on the behavioral state of the animal. TES-induced voltage gradient, as low as 1 mV/mm at the recording sites, was sufficient to phase-bias neuronal spiking. Intracellular recordings showed that both spiking and subthreshold activity were under the combined influence of TES forced fields and network activity. We suggest that TES in chronic preparations may be used for experimental and therapeutic control of brain activity

Phase Dependency of the Human Primary Motor Cortex and Cholinergic Inhibition Cancelation during Beta tACS

The human motor cortex has a tendency to resonant activity at about 20 Hz so stimulation should more readily entrain neuronal populations at this frequency. We investigated whether and how different interneuronal circuits contribute to such resonance by using transcranial magnetic stimulation (TMS) during transcranial alternating current stimulation (tACS) at motor (20 Hz) and a nonmotor resonance frequency (7 Hz). We tested different TMS interneuronal protocols and triggered TMS pulses at different tACS phases. The effect of cholinergic short-latency afferent inhibition (SAI) was abolished by 20 Hz tACS, linking cortical beta activity to sensorimotor integration. However, this effect occurred regardless of the tACS phase. In contrast, 20 Hz tACS selectively modulated MEP size according to the phase of tACS during single pulse, GABAAergic short-interval intracortical inhibition (SICI) and glutamatergic intracortical facilitation (ICF). For SICI this phase effect was more marked during 20 Hz stimulation. Phase modulation of SICI also depended on whether or not spontaneous beta activity occurred at ~20 Hz, supporting an interaction effect between tACS and underlying circuit resonances. The present study provides in vivo evidence linking cortical beta activity to sensorimotor integration, and for beta oscillations in motor cortex being promoted by resonance in GABAAergic interneuronal circuits