This study was supported by Russian Science Foundation grant (contract number: 17-11-01273). Special thanks to Andrey Afanasov and colleagues from Multifunctional Innovation Centre for Television Technics (National Research University, Higher School of Economics, Moscow, Russian Federation) for video recording and video editing.

All procedures were approved by the local research ethics committee of the Higher School of Economics (HSE), Moscow, with consent from all participants.
NOTE: Participants must report no history of implanted metal devices, neurological or psychiatric disease, drug abuse or alcoholism. TMS is used according to the most recent safety guidelines20. Subjects must be fully informed of the nature of the research and sign an informed consent form before starting the experiment. We show an entire set of equipment needed to run the online-combined tACS-TMS protocol by stimulation of the dominant M1 ( Figure 1; Table of Materials).
1. Place Electromyography (EMG) Electrodes in a Bipolar Belly-tendon Montage
<ol>
	<li>Clean the skin using a cleaning scrub under all the electrodes to achieve low skin impedance (below 10 kOhm).</li>
	<li>Place the active EMG electrode on the first dorsal interosseous (FDI) muscle, reference electrode on the bone 2 cm distally and the ground electrode more proximally on the arm.</li>
</ol>
2. Identifying the Target for the Stimulation Protocol
NOTE: Here, we use the frameless TMS navigation system to achieve a proper positioning of the TMS coil.
<ol>
	<li>Place the tracking sensors over the glabella between the eyebrows and above the nose of the participant.</li>
	<li>Open the navigation system software. Use individual participants&#39; structural T1 Magnetic Resonance Imaging (MRI) data and perform a co-registration of the participant&#39;s head and a 3D MRI head via the navigation system.</li>
	<li>Accurately, place the coil over the primary motor hand-area, the so called &#34;motor knob&#34; region (Figure 2).</li>
	<li>Start applying single pulse TMS and test MEPs; TMS is delivered by a stimulator (see Table of Materials) connected to a standard figure-of-eight 75-mm coil. To localize the &#34;hotspot&#34; of the left M1, hold the coil tangential to the scalp, with the handle pointing backward and laterally, angled at 45&#176; from the midline sagittal axis of the participant&#39;s head.</li>
	<li>Once the hotspot (i.e., the scalp point eliciting MEPs at threshold from the contralateral examined hand muscles) is found, mark it with a pencil to facilitate the application of the tACS target electrode.</li>
</ol>
3. tACS Electrodes Preparation
<ol>
	<li>Connect 2 surface saline-soaked sponge electrodes (size: 5 cm x 7 cm) to the stimulation device, which can generate electrical alternating current (e.g., Brainstim).</li>
	<li>In order to minimize skin sensation, constantly saturate the electrodes with a saline solution to keep impedances below 10 kOhm throughout the whole stimulation session.</li>
</ol>
4. tACS Protocol Set Up
<ol>
	<li>To set up the tACS protocol using the stimulator device, first check the battery status.</li>
	<li>Using the software, open a new session and manage a new stimulation protocol.
	<ol>
		<li>Name the protocol (e.g., &#34;Beta&#34;).</li>
		<li>Set the frequency of the stimulation (e.g., 20 Hz).</li>
		<li>Choose the waveform (e.g., sinusoidal).</li>
		<li>Set the total duration of the stimulation protocol (e.g., 600 s).</li>
		<li>Finally, set the intensity of stimulation (e.g., 1 mA), set offset, fade in, fade out, and phase at &#34;0&#34;. 
		NOTE: A little timing to fade in and out the stimulation (around 30 s) can be suggested, in order to avoid any adverse or uncomfortable neurosensory effects for the subject.</li>
		<li>Activate the device&#39;s &#34;Bluetooth&#34; function and upload the protocol from the software to the stimulator.</li>
	</ol>
	</li>
</ol>
5. tACS Electrodes Montage
<ol>
	<li>Place the &#34;target&#34; electrode over the scalp corresponding to the marked point. Place the &#34;reference&#34; electrode over the ipsilateral shoulder by using specific sticky tape, in a &#34;monopolar montage&#34;21.</li>
	<li>Carefully adjust the first elastic strap on the head with respect to the neuro-navigation head-sensors position. Then, by using the second strap, fix the target electrode position.</li>
	<li>Once tACS electrodes are placed both on the scalp and on the ipsilateral shoulder, connect them to the stimulator.</li>
	<li>Before the start of the stimulation session, ensure by visual inspection that position of the target electrode is centered over the marked hotspot.</li>
</ol>
6. Identifying the Resting Motor Threshold (RMT)
<ol>
	<li>Place the TMS coil over the target tACS electrode and carefully adjust the coil position over the hotspot (Figure 3) by using the neuro-navigation system.</li>
	<li>Measure the RMT accordingly to the combined tACS-TMS setup (i.e., TMS coil over the electrode). Specifically, adjust the TMS intensity with respect to the thickness of the tACS electrode in order to check for a reliable RMT.
	<ol>
		<li>Measure the RMT individually, it is defined as the minimum intensity required to induce an MEP in the FDI muscle with an amplitude of 50 mV (peak-to-peak) in 5 out of 10 trials22.</li>
	</ol>
	</li>
	<li>Set the intensity of the TMS stimulation at 110% of the RMT in order to start the experimental session.</li>
</ol>
7. Experimental Procedure
<ol>
	<li>Open the EMG software and start EMG recording.</li>
	<li>Start the tACS stimulation.</li>
	<li>During the stimulation, deliver TMS single pulses interspersed by random intervals from 3 to 5 seconds.</li>
	<li>Ensure that each session of the stimulation (e.g., 20 Hz tACS stimulation followed by a sham/another control frequency) lasts no more than 90 seconds with an inter-session interval around 3 minutes, in order to avoid possible carryover effect of the preceding stimulation frequency/condition11,13.</li>
</ol>

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</ol>

The authors have nothing to disclose.

This approach represents a unique opportunity to directly test online effects of tACS of the primary motor cortex by measuring corticospinal output through MEPs recording. However, the placement of the TMS coil over the tACS electrode represents a critical step that should be accurately performed. Therefore, we would firstly suggest experimenters find a target point by single pulse TMS, then mark it on the scalp and, only after that, place the tACS electrode over the hotspot. Moreover, the availability of a neuronavigation system crucially supports localization of an optimal target point for single pulse TMS. Before starting the procedure, ensure that the participant does not have any contraindications for tES24 and TMS20.
In addition, the thickness and position of the tACS electrode under the TMS coil can lead to a different RMT with respect to a standard procedure. Thus, it is important to measure the RMT when the TMS coil is already positioned over the tACS electrode.
The TMS-tACS online approach represents a technical advance for both basic research and clinical application. Since most of the tACS evidence has shown that effects are prominent during and not after the cessation of the stimulation, this approach may be useful to test online beneficial frequency-specific effects on patients with motor disease, such as essential tremor, dystonia, Parkinson&#39;s disease, and other motor diseases.
So far, this combined approach was used to investigate motor and visual cortex processes11,15. However, the tACS itself was shown to be a reliable technique to enhance cognitive functions such as memory and decision making14,16,25,26,27. In the future, the possibility of combining repetitive TMS (rTMS) together with tACS by manipulating different frequencies and targeting different cortical areas may help to investigate the mechanisms of the so-called &#34;neuroenhancement&#34;. Likewise, it was already shown that combination of tACS with a patterned TMS protocol, such as continuous theta burst stimulation (cTBS), resulted in an enhanced plasticity effect only when cTBS was applied in-phase with the peak of the tACS-imposed activation28. Furthermore, whereas rTMS is used as a clinical tool, its combination with tACS could lead to the development of a new clinical method for neurorehabilitation.
Although this article is focused on stimulation of M1, other cortical regions may be targeted using this combined approach. However, only stimulation of the human motor system may lead to measurable motor evoked potentials (MEPs) recorded from the peripheral muscles on the contralateral side representing a compound signal from series of descending cortico-spinal volleys with different generators29. On the other hand, other electrode deployments may offer different opportunities to investigate online inter-hemispheric effects by using concomitant bilateral tACS over left and right M1 together with single-pulse TMS. In addition, the online tACS-TMS approach may be used to target different cortical regions during a behavioral task by measuring reaction times (RT) and accuracy. On the one hand, the tACS-TMS approach offers an artifact-free methodology for the investigation of human motor functions; on the other hand, a tACS-EEG approach may offer more possibilities for the study of neural correlates of different cognitive processes by targeting a variety of cortical areas, but still with a greater number of artifacts inside the signal recordings.

Transcranial Electrical Stimulation (tES) is a neuromodulatory technique which allows the modification of neuronal states through different current waveforms1. Among different types of tES, transcranial Alternating Current Stimulation (tACS) enables the delivery of sinusoidal external oscillatory potentials in a specific frequency range and the modulation of physiological neural activity underlying perceptual, motor and cognitive processes2. Using tACS, it is possible to investigate potential causal links between endogenous oscillatory activity and brain processes.
In vivo, it has been shown that spiking neural activity is synchronized at different driving frequencies, suggesting that neuronal firing can be entrained by electrically applied fields3. In animal models, weak sinusoidal tACS entrains the discharged frequency of the widespread cortical neuronal pool4. In humans, tACS combined with online Electroencephalography (EEG) allows the induction of the so-called &#34;Entrainment&#34; effect on endogenous oscillatory activity by interacting with brain oscillations in a frequency-specific manner5. However, combining tACS with neuroimaging methods for a better understanding of the online mechanisms is still questionable because of AC-induced artifacts6. In addition, it is not possible to directly record the EEG signal over the stimulated target area without using a ring-like electrode which is a questionable solution7. Thus, there is a lack of systematic studies on this topic.
So far, there is no clear evidence about the lasting effects of tACS after stimulation cessation. Only a few studies have shown weak and unclear after-effects of tACS on the motor system8. Moreover, EEG evidence is still not clear about the after-effects of tACS9. On the other hand, most tACS studies showed prominent online effects10,11,12,13,14,15,16,17,18, which are difficult to measure at a physiological level because of technical constraints. Thus, the overall goal of our method is to provide an alternative approach to test online and frequency-dependent effects of tACS on the motor cortex (M1) by delivering single pulse Transcranial Magnetic Stimulation (TMS). TMS allows researchers to &#34;probe&#34; the physiological state of the human motor cortex19. Moreover, by recording Motor Evoked Potentials (MEP) on the subject&#39;s contralateral hand, we can investigate the effects of the ongoing tACS11. This approach lets us accurately monitor changes in corticospinal excitability by measuring MEP amplitude during online electrical stimulation delivered at different frequencies in an artifact-free fashion. In addition, this approach can also test online effects of any other waveform of tES.
To demonstrate the combined tACS-TMS effects, we will show the protocol by applying 20 Hz AC stimulation over the primary motor cortex (M1) while online neuronavigated single pulse TMS is delivered interspersed by random intervals from 3 to 5 s in order to test M1 cortical excitability.

<table><tbody><tr><td>BrainStim, high-resolution transcranial stimulator</td><td>E.M.S., Bologna, Italy</td><td>EMS-BRAINSTIM</td><td></td></tr><tr><td>Pair of 1,5m cables for connection of conductive silicone electrodes</td><td>E.M.S., Bologna, Italy</td><td>EMS-CVBS15</td><td></td></tr><tr><td>Reusable conductive silicone electrodes 50x50mm</td><td>E.M.S., Bologna, Italy</td><td>FIA-PG970/2</td><td></td></tr><tr><td>Reusable spontex sponge for electrode 50x100mm</td><td>E.M.S., Bologna, Italy</td><td>FIA-PG916S</td><td></td></tr><tr><td>Rubber belts &amp;ndash; 75 cm</td><td>E.M.S., Bologna, Italy</td><td>FIA-ER-PG905/8</td><td></td></tr><tr><td>Plastic non traumatic button</td><td>E.M.S., Bologna, Italy</td><td>FIA-PG905/99</td><td></td></tr><tr><td>Brainstim</td><td>E.M.S., Bologna, Italy</td><td></td><td></td></tr><tr><td>MagPro X100 MagOption - transcranial magnetic stimulator</td><td>MagVenture, Farum, Denmark</td><td>9016E0731</td><td></td></tr><tr><td>8-shaped coil MC-B65-HO-2</td><td>MagVenture, Farum, Denmark</td><td>9016E0462</td><td></td></tr><tr><td>Chair with neckrest</td><td>MagVenture, Farum, Denmark</td><td>9016B0081</td><td></td></tr><tr><td>Localite TMS Navigator - Navigation platform, Premium edition</td><td>Localite, GmbH, Germany</td><td>21223</td><td></td></tr><tr><td>Localite TMS Navigator - MR-based software, import data for morphological MRI (DICOM, NifTi)</td><td>Localite, GmbH, Germany</td><td>10226</td><td></td></tr><tr><td>MagVenture 24.8 coil tracker, Geom 1</td><td>Localite, GmbH, Germany</td><td>5221</td><td></td></tr><tr><td>Electrode wires for surface EMG</td><td>&amp;nbsp;EBNeuro, Italy&amp;nbsp;</td><td>6515</td><td></td></tr><tr><td>Surface Electrodes for EEG/EMG</td><td>&amp;nbsp;EBNeuro, Italy&amp;nbsp;</td><td>6515</td><td></td></tr><tr><td>BrainAmp ExG amplifier - bipolar amplifier&amp;nbsp;</td><td>Brain Products, GmbH, Germany</td><td></td><td></td></tr><tr><td>&amp;nbsp;BrainVision Recorder 1.21.0004&amp;nbsp;</td><td>Brain Products, GmbH, Germany</td><td></td><td></td></tr><tr><td>Nuprep Skin Prep Gel&amp;nbsp;</td><td>Weaver and Company, USA</td><td></td><td></td></tr><tr><td>Syringes</td><td></td><td></td><td></td></tr><tr><td>Sticky tape</td><td></td><td></td><td></td></tr><tr><td>NaCl solution</td><td></td><td></td><td></td></tr></tbody></table>

effects of transcranial alternating current stimulation on the primary motor cortex by online combined approach with transcranial magnetic stimulation

Transcranial Alternating Current Stimulation (tACS) is a neuromodulatory technique able to act through sinusoidal electrical waveforms in a specific frequency and in turn modulate ongoing cortical oscillatory activity. This neurotool allows the establishment of a causal link between endogenous oscillatory activity and behavior. Most of the tACS studies have shown online effects of tACS. However, little is known about the underlying action mechanisms of this technique because of the AC-induced artifacts on Electroencephalography (EEG) signals. Here we show a unique approach to investigate online physiological frequency-specific effects of tACS of the primary motor cortex (M1) by using single pulse Transcranial Magnetic Stimulation (TMS) to probe cortical excitability changes. In our setup, the TMS coil is placed over the tACS electrode while Motor Evoked Potentials (MEPs) are collected to test the effects of the ongoing M1-tACS. So far, this approach has mainly been used to study the visual and motor systems. However, the current tACS-TMS setup can pave the way for future investigations of cognitive functions. Therefore, we provide a step-by-step manual and video guidelines for the procedure.

The first evidence of a tACS/TMS combined approach was shown by Kanai et al. in 2010. In that study, the authors applied tACS over the primary visual cortex (V1) and demonstrated a frequency-specific modulation of the visual cortical excitability measured by online TMS-induced phosphene perception15. A more refined version of the protocol was adopted to investigate a physiological modulation of the motor cortex excitability by Feurra et al. in 2011. To do so, these authors recorded MEPs during single pulse TMS while ongoing tACS was delivered (Figure 4). Authors reported the first causal evidence of possible entrainment of 20 Hz stimulation of the endogenous idling Beta rhythm of M1 by enhancing the corticospinal output with respect to other control frequencies, control site (parietal stimulation) and control experiment (peripheral ulnar nerve experiment)11 (Figure 5).
In a following study, Feurra and collaborators showed that effects of tACS are not only frequency but also state-dependent13. By using the same combined montage, tACS was applied over the M1 under two different conditions: rest and motor imagery (subjects were asked to imagine pinch-to grip movements). In line with the previous findings11, only Beta stimulation (20 Hz) enhanced primary motor cortex excitability at rest, while during the motor imagery task the enhancement effect was prominent during theta (5 Hz) and alpha (10 Hz) stimulation. This represented the first physiological evidence of a state-dependent effect by tACS.
To date, this combined approached has been used to further study the functioning of the motor cortex (Table 1). Guerra and collaborators applied tACS-TMS, by using a similar approach, to show how specific interneuronal circuits react to the stimulation delivered at motor frequency (20 Hz) and non-motor resonance frequency (7 Hz). They showed that 20 Hz stimulation abolished the effect of cholinergic short-latency afferent inhibition (SAI), regardless of the phase of the stimulation. Interestingly, changes in glutamatergic intracortical facilitation (ICF) and GABAAergic short-interval intracortical inhibition (SICI) were phase-specific23.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/55839/55839fig1.jpg" /> 
Figure 1: List of the required materials for simultaneous tACS stimulation. Saline solution, control device, elastic straps, sponges (tACS), tACS cable wires and electrodes, syringes, sticky tape. <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55839/55839fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/55839/55839fig2.jpg" /> 
Figure 2: Neuronavigation during the tACS-TMS protocol. The red cross indicates a memorized TMS hot-spot on the primary motor cortex. The overlapping white cross indicates an online positioning of the TMS coil during the protocol, as a sign of correct orientation. <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55839/55839fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/55839/55839fig3.jpg" /> 
Figure 3: tACS-TMS on the subject&#39;s scalp. The TMS coil must be placed over the target tACS electrode. The investigator should maintain the position of the coil in accordance with the neuronavigation coordinates of the hotspot. <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55839/55839fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/55839/55839fig4.jpg" /> 
Figure 4: Schematic representation of the experimental design by using the online tACS-TMS approach. (a) Red (&#34;target&#34;) electrodes are placed on the scalp overlying the left motor cortex and the right parietal cortex (P4 position of the 10-20 International EEG System). The blue (&#34;reference&#34;) electrode is placed on the midline corresponding to the PZ (10 -20 International EEG System) position (bipolar/cephalic montage). Of note, the reference electrode of the current proposal is placed on the ipsilateral shoulder (monopolar montage), while P4 is used as a control site. (b) Neuronavigated TMS: The coil is held on the sponge electrode placed over the left M1. The colored triangles indicate the online feedback of the coil displacement from the exact target, with a tolerance of 2 mm (This figure has been modified from Feurra et al., 2011)11. <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55839/55839fig4large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/55839/55839fig5.jpg" /> 
Figure 5: Representative results. (a) Average log-transformed MEP amplitude (error bars denote Standard Error) values (raw data) obtained through different experimental conditions. Only tACS delivered at beta range (20 Hz) on the motor cortex increases the corticospinal output versus all the other conditions (baseline, 5 Hz, 10 Hz, 40 Hz, and 20 Hz on the parietal cortex). An asterisk (*) indicates a significant difference of 20 Hz stimulation with respect to all the other conditions. (b) Percentage changes versus baseline of raw MEP amplitude values (This figure has been modified from Feurra et al., 2011)11. <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55839/55839fig5large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Authors&#160;</td>
			<td>Task</td>
			<td>Frequency</td>
			<td>Intensity</td>
			<td>Electrodes position</td>
			<td>Results</td>
		</tr>
		<tr>
			<td>Feurra et al., 2011&#160;</td>
			<td>measurements of corticospinal excitability at rest</td>
			<td>5 Hz, 10 Hz, 20 Hz, 40 Hz</td>
			<td>1 mA</td>
			<td>Left M1, parietal cortex, ulnar nerve</td>
			<td>20 Hz increased MEPs size at rest</td>
		</tr>
		<tr>
			<td>Feurra et al., 2013&#160;</td>
			<td>measurements of corticospinal excitability at rest and during motor imagery&#160;</td>
			<td>5 Hz, 10 Hz, 20 Hz, 40 Hz</td>
			<td>1 mA</td>
			<td>Left M1</td>
			<td>20 Hz increased MEPs size at rest while 5 and 10 Hz increased MEPs size during motor imagery</td>
		</tr>
		<tr>
			<td>Cancelli et al., 2015</td>
			<td>measurements of corticospinal excitability at rest&#160;</td>
			<td>20Hz</td>
			<td>2.2 mA</td>
			<td>Bilateral M1</td>
			<td>Differences in cortical excitability enhancement&#160; with respect to&#160; personalized and non-personalized electrodes</td>
		</tr>
		<tr>
			<td>Guerra et al., 2016</td>
			<td>measurements of corticospinal excitability at rest</td>
			<td>7 Hz, 20 Hz</td>
			<td>1 mA</td>
			<td>Left M1</td>
			<td>20 Hz tACS modulated SICI, ICF&#160; and SAI&#160;</td>
		</tr>
	</tbody>
</table>
Table 1: tACS effects on the primary motor cortex through different conditions. Frequency, intensity, cortical site of stimulation and results.

Watch this Scientific Journal Video about Effects of Transcranial Alternating Current Stimulation on the Primary Motor Cortex by Online Combined Approach with Transcranial Magnetic Stimulation at JoVE

Effects of Transcranial Alternating Current Stimulation on the Primary Motor Cortex by Online Combined Approach with Transcranial Magnetic Stimulation

Transcranial Alternating Current Stimulation (tACS) allows the modulation of cortical excitability in a frequency-specific fashion. Here we show a unique approach which combines online tACS with single pulse Transcranial Magnetic Stimulation (TMS) in order to "probe" cortical excitability by means of Motor Evoked Potentials.

Transcranial Alternating Current Stimulation (tACS) is a neuromodulatory technique able to act through sinusoidal electrical waveforms in a specific ...

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9.0K Views.  National Research University Higher School of Economics. Transcraniële wisselstroom stimulatie (TAC's) kunnen de modulering van de corticale prikkelbaarheid in een frequentie-specifieke mode. Hier laten we een unieke aanpak die online TAC's met één puls Transcraniële magnetische stimulatie (TMS) combineert om corticale prikkelbaarheid "probe" door middel van Motor Evoked Potentials.

Video: Effects of Transcranial Alternating Current Stimulation on the Primary Motor Cortex by Online Combined Approach with Transcranial Magnetic Stimulation

Transcranial Direct Current Stimulation and Simultaneous  Functional Magnetic Resonance Imaging

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses weak electrical currents administered to the scalp to manipulate cortical excitability and, consequently, behavior and brain function. In the last decade, numerous studies have addressed short-term and long-term effects of tDCS on different measures of behavioral performance during motor and cognitive tasks, both in healthy individuals and in a number of different patient populations. So far, however, little is known about the neural underpinnings of tDCS-action in humans with regard to large-scale brain networks. This issue can be addressed by combining tDCS with functional brain imaging techniques like functional magnetic resonance imaging (fMRI) or electroencephalography (EEG).
In particular, fMRI is the most widely used brain imaging technique to investigate the neural mechanisms underlying cognition and motor functions. Application of tDCS during fMRI allows analysis of the neural mechanisms underlying behavioral tDCS effects with high spatial resolution across the entire brain. Recent studies using this technique identified stimulation induced changes in task-related functional brain activity at the stimulation site&#160;and also in more distant brain regions, which were associated with behavioral improvement. In addition, tDCS administered during resting-state fMRI allowed identification of widespread changes in whole brain functional connectivity.
Future studies using this combined protocol should yield new insights into the mechanisms of tDCS action in health and disease and new options for more targeted application of tDCS in research and clinical settings. The present manuscript describes this novel technique in a step-by-step fashion, with a focus on technical aspects of tDCS administered during fMRI.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique. It has successfully been used in basic research and clinical settings to modulate brain function in humans. This article describes the implementation of tDCS and simultaneous functional magnetic resonance imaging (fMRI), to investigate the neural basis of tDCS effects.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses weak electrical currents administered to the scalp ...

Behavior

Transcranial Magnetic Stimulation for Investigating Causal Brain-behavioral Relationships and their Time Course

Transcranial magnetic stimulation (TMS) is a safe, non-invasive brain stimulation technique that uses a strong electromagnet in order to temporarily disrupt information processing in a brain region, generating a short-lived &#8220;virtual lesion.&#8221; Stimulation that interferes with task performance indicates that the affected brain region is necessary to perform the task normally. In other words, unlike neuroimaging methods such as functional magnetic resonance imaging (fMRI) that indicate correlations between brain and behavior, TMS can be used to demonstrate causal brain-behavior relations. Furthermore, by varying the duration and onset of the virtual lesion, TMS can also reveal the time course of normal processing. As a result, TMS has become an important tool in cognitive neuroscience. Advantages of the technique over lesion-deficit studies include better spatial-temporal precision of the disruption effect, the ability to use participants as their own control subjects, and the accessibility of participants. Limitations include concurrent auditory and somatosensory stimulation that may influence task performance, limited access to structures more than a few centimeters from the surface of the scalp, and the relatively large space of free parameters that need to be optimized in order for the experiment to work. Experimental designs that give careful consideration to appropriate control conditions help to address these concerns. This article illustrates these issues with TMS results that investigate the spatial and temporal contributions of the left supramarginal gyrus (SMG) to reading.

Transcranial magnetic stimulation (TMS) is a technique for non-invasively disrupting neural information processing and measuring its effect on behavior. When TMS interferes with a task, it indicates that the stimulated brain region is necessary for normal task performance, allowing one to systematically relate brain regions to cognitive functions.

Transcranial magnetic stimulation (TMS) is a safe, non-invasive brain stimulation technique that uses a strong electromagnet in order to temporarily ...

Utilizing Transcranial Magnetic Stimulation to Study the Human Neuromuscular System

Transcranial magnetic stimulation (TMS) has been in use for more than 20 years 1, and has grown exponentially in popularity over the past decade. While the use of TMS has expanded to the study of many systems and processes during this time, the original application and perhaps one of the most common uses of TMS involves studying the physiology, plasticity and function of the human neuromuscular system. Single pulse TMS applied to the motor cortex excites pyramidal neurons transsynaptically 2 (Figure 1) and results in a measurable electromyographic response that can be used to study and evaluate the integrity and excitability of the corticospinal tract in humans 3. Additionally, recent advances in magnetic stimulation now allows for partitioning of cortical versus spinal excitability 4,5. For example, paired-pulse TMS can be used to assess intracortical facilitatory and inhibitory properties by combining a conditioning stimulus and a test stimulus at different interstimulus intervals 3,4,6-8. In this video article we will demonstrate the methodological and technical aspects of these techniques. Specifically, we will demonstrate single-pulse and paired-pulse TMS techniques as applied to the flexor carpi radialis (FCR) muscle as well as the erector spinae (ES) musculature. Our laboratory studies the FCR muscle as it is of interest to our research on the effects of wrist-hand cast immobilization on reduced muscle performance6,9, and we study the ES muscles due to these muscles clinical relevance as it relates to low back pain8. With this stated, we should note that TMS has been used to study many muscles of the hand, arm and legs, and should iterate that our demonstrations in the FCR and ES muscle groups are only selected examples of TMS being used to study the human neuromuscular system.

Transcranial magnetic stimulation (TMS) is a non-invasive tool to gain insight on the physiology and function of the human nervous system. Here, we present our TMS techniques to study cortical excitability of the upper limb and lumbar musculature.

Transcranial magnetic stimulation (TMS) has been in use for more than 20 years 1, and has grown exponentially in popularity over the past decade.  While ...

Medicine

Non-Invasive Electrical Brain Stimulation Montages for Modulation of Human Motor Function

Non-invasive electrical brain stimulation (NEBS) is used to modulate brain function and behavior, both for research and clinical purposes. In particular, NEBS can be applied transcranially either as direct current stimulation (tDCS) or alternating current stimulation (tACS). These stimulation types exert time-, dose- and in the case of tDCS polarity-specific effects on motor function and skill learning in healthy subjects. Lately, tDCS has been used to augment the therapy of motor disabilities in patients with stroke or movement disorders. This article provides a step-by-step protocol for targeting the primary motor cortex with tDCS and transcranial random noise stimulation (tRNS), a specific form of tACS using an electrical current applied randomly within a pre-defined frequency range. The setup of two different stimulation montages is explained. In both montages the emitting electrode (the anode for tDCS) is placed on the primary motor cortex of interest. For unilateral motor cortex stimulation the receiving electrode is placed on the contralateral forehead while for bilateral motor cortex stimulation the receiving electrode is placed on the opposite primary motor cortex. The advantages and disadvantages of each montage for the modulation of cortical excitability and motor function including learning are discussed, as well as safety, tolerability and blinding aspects.

Non-invasive electrical brain stimulation can modulate cortical function and behavior, both for research and clinical purposes. This protocol describes different brain stimulation approaches for modulation of the human motor system.

Non-invasive electrical brain stimulation (NEBS) is used to modulate brain function and behavior, both for research and clinical purposes. In particular, ...

Simultaneous Transcranial Alternating Current Stimulation and Functional Magnetic Resonance Imaging

Transcranial alternating current stimulation (tACS) is a promising tool for noninvasive investigation of brain oscillations. TACS employs frequency-specific stimulation of the human brain through current applied to the scalp with surface electrodes. Most current knowledge of the technique is based on behavioral studies; thus, combining the method with brain imaging holds potential to better understand the mechanisms of tACS. Because of electrical and susceptibility artifacts, combining tACS with brain imaging can be challenging, however, one brain imaging technique that is well suited to be applied simultaneously with tACS is functional magnetic resonance imaging (fMRI). In our lab, we have successfully combined tACS with simultaneous fMRI measurements to show that tACS effects are state, current, and frequency dependent, and that modulation of brain activity is not limited to the area directly below the electrodes. This article describes a safe and reliable setup for applying tACS simultaneously with visual task fMRI studies, which can lend to understanding oscillatory brain function as well as the effects of tACS on the brain.

Transcranial alternating current stimulation (tACS) is a promising tool for noninvasive investigation of brain oscillations, though its effects are not completely understood. This article describes a safe and reliable setup for applying tACS simultaneously with functional magnetic resonance imaging, which can increase understanding oscillatory brain function and effects of tACS.

Transcranial alternating current stimulation (tACS) is a promising tool for noninvasive investigation of brain oscillations. TACS employs ...

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 stimulation. The combination of electroencephalography (EEG) and transcranial magnetic stimulation (TMS) in a real-time brain state-dependent stimulation system allows the study of relations of dynamics of brain activity, cortical excitability, and plasticity induction. Here, we demonstrate a newly developed method to synchronize the timing of brain stimulation with the phase of ongoing EEG oscillations using a real-time data analysis system. This real-time EEG-triggered TMS of the human motor cortex, when TMS is synchronized with the surface EEG negative peak of the sensorimotor &#181;-alpha (8-14 Hz) rhythm, has shown differential corticospinal excitability and plasticity effects. The utilization of this method suggests that real-time information about the instantaneous brain state can be used for efficacious plasticity induction. Additionally, this approach enables personalized EEG-synchronized brain stimulation which may lead to the development of more effective therapeutic brain stimulation protocols.

This paper describes real-time electroencephalography-triggered transcranial magnetic stimulation to study and modulate human brain networks.

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 ...

The Use of Magnetic Resonance Spectroscopy as a Tool for the Measurement of Bi-hemispheric Transcranial Electric Stimulation Effects on Primary Motor Cortex Metabolism

Transcranial direct current stimulation (tDCS) is a neuromodulation technique that has been increasingly used over the past decade in the treatment of neurological and psychiatric disorders such as stroke and depression. Yet, the mechanisms underlying its ability to modulate brain excitability to improve clinical symptoms remains poorly understood 33. To help improve this understanding, proton magnetic resonance spectroscopy (1H-MRS) can be used as it allows the in vivo quantification of brain metabolites such as &#947;-aminobutyric acid (GABA) and glutamate in a region-specific manner 41. In fact, a recent study demonstrated that 1H-MRS is indeed a powerful means to better understand the effects of tDCS on neurotransmitter concentration 34. This article aims to describe the complete protocol for combining tDCS (NeuroConn MR compatible stimulator) with 1H-MRS at 3 T using a MEGA-PRESS sequence. We will describe the impact of a protocol that has shown great promise for the treatment of motor dysfunctions after stroke, which consists of bilateral stimulation of primary motor cortices 27,30,31. Methodological factors to consider and possible modifications to the protocol are also discussed.

This article aims to describe a basic protocol for combining transcranial direct current stimulation (tDCS) with proton magnetic resonance spectroscopy (1H-MRS) measurements to investigate the effects of bilateral stimulation on primary motor cortex metabolism.

Transcranial direct current stimulation (tDCS) is a neuromodulation technique that has been increasingly used over the past decade in the treatment of ...

Combined Transcranial Magnetic Stimulation and Electroencephalography of the Dorsolateral Prefrontal Cortex

Transcranial magnetic stimulation (TMS) is a non-invasive method that produces neural excitation in the cortex by means of brief, time-varying magnetic field pulses. The initiation of cortical activation or its modulation depends on the background activation of the neurons of the cortical region activated, the characteristics of the coil, its position and its orientation with respect to the head. TMS combined with simultaneous electrocephalography (EEG) and neuronavigation (nTMS-EEG) allows for the assessment of cortico-cortical excitability and connectivity in almost all cortical areas in a reproducible manner. This advance makes nTMS-EEG a powerful tool that can accurately assess brain dynamics and neurophysiology in test-retest paradigms that are required for clinical trials. Limitations of this method include artifacts that cover the initial brain reactivity to stimulation. Thus, the process of removing artifacts may also extract valuable information. Moreover, the optimal parameters for dorsolateral prefrontal (DLPFC) stimulation are not fully known and current protocols utilize variations from the motor cortex (M1) stimulation paradigms. However, evolving nTMS-EEG designs hope to address these issues. The protocol presented here introduces some standard practices for assessing neurophysiological functioning from stimulation to the DLPFC that can be applied in patients with treatment resistant psychiatric disorders that receive treatment such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), magnetic seizure therapy (MST) or electroconvulsive therapy (ECT).

The protocol presented here is for TMS-EEG studies utilizing intracortical excitability test-retest design paradigms. The intent of the protocol is to produce reliable and reproducible cortical excitability measures for assessing neurophysiological functioning related to therapeutic interventions in the treatment of neuropsychiatric diseases such as major depression.

Transcranial magnetic stimulation (TMS) is a non-invasive method that produces neural excitation in the cortex by means of brief, time-varying magnetic ...

The Combined Use of Transcranial Direct Current Stimulation and Robotic Therapy for the Upper Limb

Neurologic disorders such as stroke and cerebral palsy are leading causes of long-term disability and can lead to severe incapacity and restriction of daily activities due to lower and upper limb impairments. Intensive physical and occupational therapy are still considered main treatments, but new adjunct therapies to standard rehabilitation that may optimize functional outcomes are being studied.
Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that polarizes underlying brain regions through the application of weak direct currents through electrodes on the scalp, modulating cortical excitability. Increased interest in this technique can be attributed to its low cost, ease of use, and effects on human neural plasticity. Recent research has been performed to determine the clinical potential of tDCS in diverse conditions such as depression, Parkinson&#39;s disease, and motor rehabilitation after stroke. tDCS helps enhance brain plasticity and seems to be a promising technique in rehabilitation programs.
A number of robotic devices have been developed to assist in the rehabilitation of upper limb function after stroke. The rehabilitation of motor deficits is often a long process requiring multidisciplinary approaches for a patient to achieve maximum independence. These devices do not intend to replace manual rehabilitation therapy; instead, they were designed as an additional tool to rehabilitation programs, allowing immediate perception of results and tracking of improvements, thus helping patients to stay motivated.
Both tDSC and robot-assisted therapy are promising add-ons to stroke rehabilitation and target the modulation of brain plasticity, with several reports describing their use to be associated with conventional therapy and the improvement of therapeutic outcomes. However, more recently, some small clinical trials have been developed that describe the associated use of tDCS and robot-assisted therapy in stroke rehabilitation. In this article, we describe the combined methods used in our institute for improving motor performance after stroke.

The combined use of transcranial direct current stimulation and robotic therapy as an add-on for conventional rehabilitation therapy may result in improved therapeutic outcomes due to modulation of brain plasticity. In this article, we describe the combined methods used in our institute for improving motor performance after stroke.

Neurologic disorders such as stroke and cerebral palsy are leading causes of long-term disability and can lead to severe incapacity and restriction of ...

Measuring and Manipulating Functionally Specific Neural Pathways in the Human Motor System with Transcranial Magnetic Stimulation

Understanding interactions between brain areas is important for the study of goal-directed behavior. Functional neuroimaging of brain connectivity has provided important insights into fundamental processes of the brain like cognition, learning, and motor control. However, this approach cannot provide causal evidence for the involvement of brain areas of interest. Transcranial magnetic stimulation (TMS) is a powerful, noninvasive tool for studying the human brain that can overcome this limitation by transiently modifying brain activity. Here, we highlight recent advances using a paired-pulse, dual-site TMS method with two coils that causally probes cortico-cortical interactions in the human motor system during different task contexts. Additionally, we describe a dual-site TMS protocol based on cortical paired associative stimulation (cPAS) that transiently enhances synaptic efficiency in two interconnected brain areas by applying repeated pairs of cortical stimuli with two coils. These methods can provide a better understanding of the mechanisms underlying cognitive-motor function as well as a new perspective on manipulating specific neural pathways in a targeted fashion to modulate brain circuits and improve behavior. This approach may prove to be an effective tool to develop more sophisticated models of brain-behavior relations and improve diagnosis and treatment of many neurological and psychiatric disorders.

This article describes new approaches to measure and strengthen functionally specific neural pathways with transcranial magnetic stimulation. These advanced noninvasive brain stimulation methodologies can provide new opportunities for the understanding of brain-behavior relations and development of new therapies to treat brain disorders.

Understanding interactions between brain areas is important for the study of goal-directed behavior. Functional neuroimaging of brain connectivity has ...

Effects of Transcranial Alternating Current Stimulation on the Primary Motor Cortex by Online Combined Approach with Transcranial Magnetic Stimulation

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