Characterizing low-frequency artifacts during transcranial temporal interference stimulation (tTIS)

Transcranial alternating current stimulation (tACS) is a well-established brain stimulation technique to modulate human brain oscillations. However, due to the strong electro-magnetic artifacts induced by the stimulation current, the simultaneous measurement of tACS effects during neurophysiological recordings in humans is challenging. Recently, transcranial temporal interference stimulation (tTIS) has been introduced to stimulate neurons at depth non-invasively. During tTIS, two high-frequency sine waves are applied, that interfere inside the brain, resulting in amplitude modulated waveforms at the target frequency. Given appropriate hardware, we show that neurophysiological data during tTIS may be acquired without stimulation artifacts at low-frequencies. However, data must be inspected carefully for possible low-frequency artifacts. Our results may help to design experimental setups to record brain activity during tTIS, which may foster our understanding of its underlying mechanisms.</p

Evaluating non-linear transfer characteristics of AM-tACS hardware setups

This repository provides raw data and scripts used to evaluate non-linear properties of tACS stimulation and recording harware. These non-linearities can lead to spurious low-frequency artifacts during amplitude modulated transcranial alternating current stimulation. For details see: Kasten, F.H., Negahbani, E., Fröhlich, F., Herrmann, C.S., Non-linear transfer characteristics of stimulation and recording hardware account for spurious low-frequency artifacts during amplitude modulated transcranial alternating current stimulation (AM-tACS), NeuroImage (2018), doi: 10.1016/j.neuroimage.2018.05.068. https://www.sciencedirect.com/science/article/pii/S1053811918304944 If you find this code and/or data useful, please consider citing the above reference

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

Amplitude modulated transcranial alternating current stimulation (AM-TACS) efficacy evaluation via phosphene induction

Amplitude modulated transcranial alternating current stimulation (AM-tACS) is a novel method of electrostimulation which enables the recording of electrophysiological signals during stimulation, thanks to an easier removable stimulation artefact compared to classical electrostimulation methods. To gauge the neuromodulatory potential of AM-tACS, we tested its capacity to induce phosphenes as an indicator of stimulation efficacy. AM-tACS was applied via a two-electrode setup, attached on FpZ and below the right eye. AM-tACS waveforms comprised of different carrier (50 Hz, 200 Hz, 1000 Hz) and modulation frequencies (8 Hz, 16 Hz, 28 Hz) were administered with at maximum 2 mA peakto- peak stimulation strength. TACS conditions in the same frequencies were used as a benchmark for phosphene induction. AM-tACS conditions using a 50 Hz carrier frequency were able to induce phosphenes, but with no difference in phosphene thresholds between modulation frequencies. AM-tACS using a 200 Hz or 1000 Hz carrier frequency did not induce phosphenes. TACS conditions induced phosphenes in line with previous studies. Stimulation effects of AM-tACS conditions were independent of amplitude modulation and instead relied solely on the carrier frequency. A possible explanation may be that AM-tACS needs higher stimulation intensities for its amplitude modulation to have a neuromodulatory effect

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

Novel mechanisms of DC and kilohertz electrical stimulation

Transcranial electrical stimulation is a promising technique where a weak electrical current is applied to the scalp with the goal of modulating brain activity. Understanding the cellular mechanism of direct current (DC) and kilohertz (kHz) electrical stimulation is of broad interest in neuromodulation. More specifically, there is a large mismatch between enthusiasm for clinical applications of the method and understanding of DC and kHz novel mechanisms of action. This dissertation is centered around two main fundamental aims: 1) systematic study of the acute and long-term effects of kilohertz electrical stimulation and amplitude-modulated waveform with kHz carrier frequency using a well-established animal model, hippocampal brain slice, 2) study the effect of tDCS on water exchange rate across the blood-brain barrier using an advanced MRI imaging technique in a healthy population to investigate effect of tDCS stimulation on neurovascular units. The neuronal membrane has a well-established low pass filtering characteristic. This feature attenuates the sensitivity of the nervous system to any waveforms with high-frequency components. On the contrary, kilohertz stimulation has recently revolutionized spinal cord stimulation and even generated promising results in transcranial electrical stimulation. Investigating the effect of low kilohertz stimulation for neuromodulation is of huge interest. In chapters 2 and 3, several experimental designs are used to systematically investigate the frequency and dose-response of neuronal activity to unmodulated and amplitude modulated waveforms in low kilohertz range. The results support the theory of membrane attenuation of high-frequency stimulation. This dissertation provides the first direct in vitro evidence on acute effects of kilohertz electrical stimulation on modulating gamma oscillation using both unmodulated and Amplitude-modulated waveforms. While supported by membrane characteristics of neurons, we uncovered that using low kilohertz stimulation diminishes the sensitivity of hippocampal neurons to electrical stimulation. Moreover, Amplitude-Modulated waveforms can generate a different pattern of modulation with even higher sensitivity to stimulation. However, the required electric field, in this case, is still significantly higher than low-frequency stimulation methods such as tACS. Effects of DC stimulation have been studied in neuronal depolarization/hyperpolarization, synaptic plasticity, and neuronal network modulation. Recent evidence suggests that DC stimulation can induce polarity-dependent water exchange rate across the blood-brain barrier (BBB) in cell culture experiments through a mechanism called electroosmosis. Modulating water exchange rate across BBB is of broad interest in neurological diseases such as dementia, Alzheimer’s, and stroke where the brain clearance system is disrupted. Investigating the effect of electrical stimulation on water exchange across BBB can potentially lead to complimentary treatment options. In chapter 4, an advanced MRI technique was used to investigate induced changes in cerebral blood flow (CBF) and water exchange rate across BBB during stimulation in areas under electrodes. Contrary to our hypothesis, we could not resolve an effect in the water exchange rate across BBB. In conclusion, in our efforts to investigate effects of high frequency stimulation we found that sensitivity of neuronal networks to oscillating electrical stimulation is governed by time constant of neuronal membrane. Moreover, neuronal networks are selective to different kilohertz waveforms (i.e., amplitude modulated) and this is governed by a nonlinear adaptive mechanism present in the network. For the effect of DC stimulation on neurovascular units, we hypothesized that stimulation affects water exchange rate across BBB through a mechanism known as electroosmosis which is a very small portion of a large water exchange across BBB in active transport. We believe that this may be the answer to our negative results in experiments

A Comparison of Closed Loop vs. Fixed Frequency tACS on Modulating Brain Oscillations and Visual Detection

Transcranial alternating current stimulation has emerged as an effective tool for the exploration of brain oscillations. By applying a weak alternating current between electrodes placed on the scalp matched to the endogenous frequency, tACS enables the specific modulation of targeted brain oscillations This results in alterations in cognitive functions or persistent physiological changes. Most studies that utilize tACS determine a fixed stimulation frequency prior to the stimulation that is kept constant throughout the experiment. Yet it is known that brain rhythms can encounter shifts in their endogenous frequency. This could potentially move the ongoing brain oscillations into a frequency region where it is no longer affected by the stimulation, thereby decreasing or negating the effect of tACS. Such an effect of a mismatch between stimulation frequency and endogenous frequency on the outcome of stimulation has been shown before for the parietal alpha-activity. In this study, we employed an intermittent closed loop stimulation protocol, where the stimulation is divided into short epochs, between which an EEG is recorded and rapidly analyzed to determine a new stimulation frequency for the next stimulation epoch. This stimulation protocol was tested in a three-group study against a classical fixed stimulation protocol and a sham-treatment. We targeted the parietal alpha rhythm and hypothesized that this setup will ensure a constant close match between the frequencies of tACS and alpha activity. This closer match should lead to an increased modulation of detection of visual luminance changes depending on the phase of the tACS and an increased rise in alpha peak power post stimulation when compared to a protocol with fixed pre-determined stimulation frequency. Contrary to our hypothesis, our results show that only a fixed stimulation protocol leads to a persistent increase in post-stimulation alpha power as compared to sham. Furthermore, in none of the stimulated groups significant modulation of detection performance occurred. While the lack of behavioral effects is inconclusive due to the short selection of different phase bins and trials, the physiological results suggest that a constant stimulation with a fixed frequency is actually beneficial, when the goal is to produce persistent synaptic changes

Using Transcranial Alternating Current Stimulation (tACS) to Improve Romantic Relationships Can Be a Promising Approach

The romantic relationship refers to the specific relationship in which partners are dependent upon each other to obtain satisfactory outcomes and facilitate the pursuit of their most important needs and goals. Satisfying romantic relationships is a strong predictor of better psychological well-being, better physical health, and longer life expectancy. However, romantic relationships are not all smooth-sailing and lovers are often confronted with a variety of unavoidable issues that constantly challenge the stability of their romantic relationships. Dissatisfying romantic relationships are harmful and even destructive. Dyads of lovers engage in a variety of efforts to protect and maintain their romantic relationships based on qualitative research methods including theories- and psychological consultation-based approaches. Unfortunately, those existing approaches do not seem to effectively improve romantic relationships. Thus, it is necessary to seek an efficient approach regulating dyads of lovers in romantic relationships simultaneously. Transcranial alternating current stimulation (tACS) with advantages over existing approaches satisfies this purpose. We discuss the practicability of tACS in detail, as well as why and how tACS can be utilized to improve romantic relationships. In summary, this review firstly introduced the concept of romantic relationship and the necessity of enhancing it. Then, it discussed methods to improve romantic relationships including some existing approaches. This review next discussed the practicability of using tACS to improve romantic relationships. Finally, it shone a spotlight on potential future directions for researches aiming to improve romantic relationships