The authors have no acknowledgements.

This protocol was approved by the UCL Ethics Review Board (#249/001) for non-invasive brain stimulation of neurologically normal human volunteers.
1. Create the TMS protocol
Almost all TMS experiments in cognitive neuroscience use bi-phasic stimulation in conjunction with a figure-of-eight shaped coil. This provides the ability to deliver rapid trains of pulses (&#62; 1 Hz) and target a cortical site as precisely as possible. It is possible to use mono-phasic stimulation35 or a different coil shape36, but here the standard configuration was applied.
<ol>
	<li>Choose a frequency and duration of stimulation. 
	NOTE: A common choice in cognitive neuroscience is to use 10 Hz stimulation for 500 msec from onset of the stimulus37-40.</li>
	<li>Choose a level of intensity based on extensive pilot testing. Hold it constant across participants. 
	NOTE: For the equipment used here, commonly used intensities range between 50 - 70% of the maximum stimulator output11,41-44.</li>
	<li>Choose an inter-trial interval. For both practical and safety reasons, separate the stimulation trials by a minimum of 3 - 5 sec27,45.</li>
</ol>
2. Perform Head Registration
<ol>
	<li>Acquire a high-resolution, T1-weighted anatomical magnetic resonance imaging (MRI) scan for each participant on a separate session prior to the TMS. Include the fiducial points in the image that will be used in step 2.3.&#160;</li>
	<li>Load the scan into the frameless stereotaxy system before the TMS session to enable accurate targeting of stimulation sites in each participant. Mark the stimulation sites on the head at the beginning of the experiment or monitor continually throughout the experiment.</li>
	<li>Mark four fiducial points on the participant&#8217;s image. Typically these include the tip of the nose, the bridge of the nose, and the notch above the tragus of each ear.</li>
	<li>Provide the participant information about TMS in order for them to give informed consent to participate in the experiment.</li>
	<li>Ask the participant to complete a TMS Safety Screen form that has been approved by the Institutional Review Board.&#160; 
	NOTE: Permanent contradictions to TMS include a personal or family history of epilepsy, a clinical history of neurological or psychiatric problems, or implanted medical devices such as a cardiac pacemaker or cochlear implants. Not following TMS safety requirements can potentially induce syncope and seizure.</li>
	<li>Place the subject tracker on the participant&#8217;s head; it will act as a reference when measuring fiducial points. Touch each fiducial point on the subject&#8217;s head with a pointer that comes with the stereotaxy system and save the corresponding co-ordinates on the computer. Calibrate subject&#8217;s head with the MRI image. Check the quality of registration and repeat the process if necessary.</li>
	<li>Ask the participant to wear earplugs during stimulation to attenuate the sound of the coil discharge and avoid damage to participants&#8217; hearing46.</li>
	<li>Set up the TMS machine according to the choices made in Section 1.&#160;</li>
	<li>Introduce the participant to stimulation before testing to ensure that the participant is familiarized with its sensation and tolerates well. First demonstrate stimulation on the researcher&#8217;s arm and then on the participant&#8217;s arm to acclimate the person with the sensation. 
	NOTE: This is especially important for participants who are experiencing TMS for the first time.</li>
	<li>Demonstrate the stimulation protocol on each of the testing sites as the sensation may be different at different locations. Place the coil on the first site as identified by the frameless stereotaxy system such that the coil is tangential to the scalp and the line of maximum magnetic flux intersects the stimulated site.&#160; 
	NOTE: Stimulation sometimes affects facial nerves or muscles and may lead to discomfort so it is important to test whether the participant tolerates it well.</li>
</ol>
3. Perform Functional Localization
<ol>
	<li>Optimize the stimulation site by customizing it to each participant. Mark several potential stimulation sites within the brain region of interest on the participant&#8217;s structural image. Locate targets at least 10mm from each other given the spatial resolution of TMS47 using a grid or anatomical marking (Figure 1).</li>
	<li>Choose a localizer task that taps into the cognitive function of interest and has a measurable behavior (e.g., reaction times, accuracy, eye-movements). Repeat the task multiple times when testing the possible sites and create different versions of the task to avoid constant repetition of the stimuli.</li>
	<li>Allow the participant to practice the task without stimulation until they are comfortable with it. Then introduce a second practice session with TMS randomly (or pseudo-randomly) presented on 50% of the trials so that the participant gets used to performing the task without being distracted by stimulation.</li>
	<li>Choose a testing site and run one version of the localizer task. Immediately afterwards check the results to see whether stimulation affected performance.&#160; 
	NOTE: In many cases, stimulating an &#8220;incorrect&#8221; site will actually facilitate responses relative to no stimulation due to inter-sensory facilitation2, in this case due to hearing the clicks and feeling the sensation of stimulation in the scalp. In addition, large effects of stimulation (i.e., over 100 msec) are often artifactual and require re-testing. If they replicate and are specific to a particularly testing site, then they may be genuine effects. Be sure to choose a robust measure of a TMS effect to be confident in localization.&#160;</li>
	<li>If no effect is observed, choose a new testing site and repeat, otherwise test the same site again to determine whether it replicates. Test multiple sites back-to-back in the same session to ensure that they do not all produce an effect as this would indicate a non-specific TMS effect. Counterbalance the order that sites are stimulated across participants.</li>
</ol>
4. Main Task
<ol>
	<li>After localization and in the same session, run the main experiment using the target site that was functionally localized. 
	NOTE: This will involve a different task to the one used in localization but one that shares the key process of interest. For example, a rhyme judgment task can be used for localizing an area sensitive to processing the sounds of words while a homophone judgment task might be used for the main experiment. In this example, both tasks require phonological processing of written words although the specific task demands and stimuli differ.</li>
	<li>Include sufficient control conditions to rule out non-specific effects of TMS.</li>
	<li>Test the same site on a control task that does not include the process of interest to demonstrate functional specificity in processing.</li>
	<li>Test a different site on the main task to demonstrate anatomical specificity of the effect.</li>
	<li>Include additional control conditions such as sham TMS, control stimuli, or multiple time windows.</li>
	<li>Conduct a traditional &#8220;virtual lesion&#8221; experiment using the same TMS parameters used during localization (e.g., intensity, frequency, and duration of stimulation). For chronometric TMS experiment, use the same intensity but replace the train of pulses used during localization by either a single48 or double pulse49 delivered at different onset latencies.</li>
</ol>

The authors declare that they have no competing financial interests.

This article presents a protocol for assessing the causal and temporal involvement of brain regions in cognitive processes using online TMS. This discussion highlights first the critical steps for creating a successful TMS protocol and then the limitations that need to be considered when designing a TMS experiment.
Because TMS protocols have a large number of free parameters, ensuring the optimal stimulation parameters is a critical step in preparing a TMS experiment. Normally, this is achieved through extensive pilot testing in order to determine the stimulation frequency, duration, intensity, inter-trial interval, and coil orientation necessary to produce robust effects. To create an effective &#8220;virtual lesion&#8221; the frequency must induce a robust effect that covers a sufficiently large time window to encompass the cognitive process of interest. As a result, both frequency and duration vary across studies. Similarly, the &#8220;right&#8221; stimulation intensity is one that ensures the magnetic field affects neural processing in the target brain region and here the main factor is the distance from the coil to the stimulation site51. Many studies identify the intensity of stimulation necessary to produce a motor response when stimulating the hand area of primary motor cortex and use this to normalize intensity across participants52,53-55. This measure, however, is not a reliable index of the optimal intensity for non-motor areas42,51,56. Another option is to use the same intensity for all participants. The chosen intensity should be effective across all pilot subjects after experimenting with a range of stimulation intensities. Additionally, the coil orientation is an important parameter that requires consideration. The specific coil orientation affects the distribution of the induced electric field within the stimulated neuronal population and therefore may influence behavior. In general, published protocols can provide a starting point that is iteratively modified during pilot testing to suit the specific experiment. Often, however, information about this pilot testing is omitted from the final manuscript, which has the unfortunate effect of hiding some key aspects of the protocol design process.
Choosing a localization procedure is also essential to ensure that stimulation is administered to the optimal site. Although many studies have successfully localized stimulation sites using anatomy-based methods that target a single location across individual participants 57,58, customizing the stimulation site for each subject individually reduces between-subject variance in behavioral results yielding a more efficient method31. Here we presented a TMS-based functional localization procedure that offers advantages over fMRI-based localization. Specifically, it avoids the problem of different spatial biases between fMRI (i.e., draining veins59) and TMS (i.e., the orientation of axons within the magnetic field6,60) that may result in the same neural response being localized to different locations. In addition, it is well known that the specific location of activation &#8220;peaks&#8221; in fMRI can vary considerably, making them sub-optimal as TMS targets55,61. Even so, a variety of different localization procedures are demonstrably effective, so the specific choice is less important that ensuring that whichever method is used provides reliable, reproducible effects.
Although the experiment data presented here used reaction times as the dependent measure, there are many other options available. For instance, some studies use accuracy instead9,12,62. In these cases, normal performance without TMS is already below ceiling levels so the disruption induced by stimulation is reflected in the accuracy scores. Other studies have measured the effects of stimulation on eye movements63,64. Most cognitive neuroscience experiments with TMS, however, use reaction times as their dependent measure13,48,65,66. Typically, the effects are on the order of tens of msec, or roughly a 10% change in reaction times67. Whatever dependent measure is used should be robust and consistent so that relatively small changes can be easily observed.
Like any experimental technique, TMS has important limitations that need to be considered when choosing this methodology. The most common ones are: i) the spatial resolution of TMS, ii) the non-specific effects associated with stimulation, and iii) safety aspects of the methodology. First, TMS has a limited depth of stimulation because the magnetic field reduces in intensity the further away it is from the coil. Consequently, it is most effective at stimulating brain regions near scalp (~2 - 3 cm)68,69 and is ineffective in stimulating deep brain structures. As a result, the only regions directly accessible to TMS are limited to the cortical mantle, although different shaped coils are being developed to reach deeper regions such as the basal ganglia69. TMS also has a spatial resolution of approximately 0.5 - 1 cm47,70-72. Thus, the method cannot be used to investigate the functional contributions from fine-grained spatial structures such as cortical columns.
A second limitation of TMS is that stimulation introduces concurrent sensory side effects as a result of the rapidly-changing magnetic field. Most notably, each magnetic pulse is accompanied by an auditory click and a tapping sensation. Therefore TMS may be inappropriate for certain auditory or somatosensory experiments where these side effects may interfere with task performance. Note, however, that online TMS has been used successfully in some auditory experiments73,74 and is therefore feasible in at least some tasks. Another consideration is that the intensity of the sensory effects differs across head locations. For example, stimulation that is administered to a location close to the ear will sound louder than locations further away. Similarly more ventral locations on the head produce greater muscle contraction than dorsal areas75,76. Because these site differences can induce experimental confounds, it is important to use either a control site with similar side-effects to the main site such as contralateral homologues77 or include control conditions/tasks that do not tap into the process of interest24,62,73,78,79.
Finally, safety considerations must always be taken into account when designing TMS experiments as it can potentially induce syncope and seizures27. To minimize this risk, internationally accepted guidelines for stimulation intensity, frequency, and duration exists, as well as for the total number of pulses and the inter-trial intervals27,28. Protocols that stay within these guidelines are believed to be safe for neurologically normal participants. It is worth noting, however, that these are as yet incomplete and that often novel TMS protocols are introduced that also prove safe. In general, the evidence suggests that when published guidelines are followed, TMS is a safe procedure with no dangerous side effects. One consequence of these limits, however, is that behavioral protocols will often need to be adjusted before they can be used with TMS. This has implications for several aspects of the design, including the length of the experiment, number of trials, number of conditions and stimulation sites that can be tested. Some of these limitations may be overcome by splitting the experiment into separate sessions such as testing different stimulation sites on different days. In those cases, it is important to ensure that localization and testing of a site are done within the same session. This minimizes experimental variance by maximizing the accuracy of the targeting. When deciding whether to use one or more testing session, the fundamental limitation is the safety of the participant &#8211; specifically, the amount of stimulation that is safe in a single session. The total stimulation involves familiarization, practice, localization (if using TMS), and testing, potentially over multiple sites, and critically depends on the number of trials per condition. Where this figure exceeds the guidelines for a single session, it is necessary to break the experiment into multiple sessions, conducted a minimum of 24 hr apart. There are no hard-and-fast rules regarding the minimum number of trials necessary for TMS experiments, but like any experiment, these can be computed using standard power calculations based on the effect size, variance, &#945;-level (typically 0.05) and desired sensitivity. Often reasonable estimates of the effect size and variance are available as a result of the extensive pilot testing done to optimize the experimental protocol.
In summary, TMS has become an important tool with broad applications to cognitive neuroscience. This article provides a basic protocol for online TMS in conjunction with a behavioral task for investigating causal brain-behavioral relationships both in &#8220;virtual lesion&#8221; mode and also a chronometric tool for exploring the temporal dynamics of regionally-specific neural information processing.

Transcranial magnetic stimulation (TMS) is a safe and non-invasive tool used for brain stimulation. It uses a rapidly changing electric current within a conducting coil to generate a strong, but relatively focal, magnetic field. When applied to the scalp, the magnetic field induces electrical activity in the underlying brain tissue, temporarily disrupting local cortical information processing. This transient interference effectively creates a short-lasting &#8220;virtual lesion&#8221;1,2. This technique offers a non-invasive method for drawing causal brain-behavior inferences and investigating the temporal dynamics of online neural information processing in both healthy adults and neurological patients.
By selectively interfering with regionally-specific cortical processing, TMS can be used to draw causal links between brain regions and specific behaviors3,4. That is, if stimulating a cortical area significantly affects task performance relative to appropriate control conditions, this indicates that the stimulated area is necessary to perform the task normally. Causal inferences of this sort are one of the major advantages of TMS over neuroimaging methods such as functional magnetic resonance imaging (fMRI) or positron emission tomography (PET). Unlike neuroimaging techniques that measure neural activity and correlate it with behavior, TMS offers the opportunity to perturb neural information processing and measure its effects on behavior. In this sense, it is more like traditional lesion-deficit analyses in patients with brain damage except that TMS is non-invasive and the effects are temporary and reversible. TMS also has several advantages over lesion studies. For instance, the effects of stimulation are generally more spatially precise than naturally occurring lesions, which are often large and vary greatly across patients. In addition, participants can be used as their own controls, thereby avoiding the issue of potential differences in pre-morbid abilities between patients and controls. Finally, there is insufficient time for functional reorganization to take place during TMS, meaning that recovery processes are unlikely to confound the results5. In other words, TMS offers a powerful tool for investigating causal brain-behavior relations that complements correlative techniques such as functional neuroimaging.
TMS can also be used to investigate the time course of neural information processing by using very short bursts of stimulation and varying the onset of stimulation6. Typically this involves either a single or double pulse TMS delivered to a region at different points of time within a trial. Because the effect of an individual TMS pulse occurs immediately and lasts somewhere between 5 and 40 msec7-10, this enables the researcher to map the temporal dynamics of regional neuronal activity including its onset, duration, and offset11,12. The duration of this disruption limits the temporal resolution of the technique to 10s of msec, roughly an order of magnitude coarser than electroencephalography (EEG) and magnetoencephalography (MEG). On the other hand, the timings observed in chronometric TMS studies tend to match those from invasive neurophysiological recordings better than EEG and MEG9,13. Presumably this is because EEG and MEG measure large scale neuronal synchrony that lags behind the earliest onset of activity14. In addition, like fMRI and PET, EEG and MEG are correlative measures of whole brain activity whereas chronometric TMS can not only provide important information about regional temporal dynamics but also about the necessity of the region for a given behavior.
Although TMS was originally developed for investigating the physiology of the motor system15, it was quickly adopted as a valuable tool for cognitive neuroscience. One of its earliest uses as a &#8220;virtual lesion&#8221; technique was to induce speech arrest by stimulating the left inferior frontal cortex16-18. The results confirmed the importance of Broca&#8217;s area for speech production and suggested a potential alternative to Wada testing to determine language dominance subsequent to neurosurgical interventions16,19. Now TMS is used in virtually all areas of cognitive neuroscience including attention20, memory21, visual processing22, action planning23, decision making24, and language processing25. Typically TMS induces either increased error rates or slower reaction times (RTs), both of which are taken as indicators of causal relations between brain and behavior3,4. Some studies use TMS in both its virtual lesion mode and as a chronometric tool. For example, Pitcher and colleagues11 first showed that repetitive TMS (rTMS) delivered to the occipital face area disrupted accurate facial discrimination and then used chronometric TMS to determine that this effect was only present when TMS was delivered at 60 and 100 msec, demonstrating that this particular brain region processes face-part information at an early stage of face recognition. In all of the examples mentioned here, TMS is administered &#8220;on-line&#8221;, that is during task performance, so that the effects of TMS are immediate and short lived (i.e., the effects last as long as the duration of stimulation). This contrasts with &#8220;off-line&#8221; TMS which involves either long runs of low frequency stimulation21 or short bursts of patterned stimulation26 before starting a task. In off-line TMS the effects last well beyond the duration of the TMS application itself. This article focuses exclusively on the &#8220;on-line&#8221; approach.
The initial steps in preparing any TMS experiment include identifying a stimulation protocol and choosing a localization method. Stimulation parameters include intensity, frequency and duration of TMS and are constrained by internationally defined safety requirements27,28. Each TMS experiment also requires a suitable localization procedure for positioning and orienting the coil accurately over the stimulation site. Localization can be based on standard space coordinates29 or 10 - 20 localization system30, but typically is customized to each individual participant31. For the latter, there are many options that include targeting stimulation based on each individual&#8217;s anatomy32, functionally localizing using fMRI33 or functionally localizing using TMS34. The protocol presented here advocates functional localization with TMS as part of a general protocol for on-line TMS experiments. Then an illustrative example is presented of how TMS can be used to investigate the functional contributions of the left supramarginal gyrus (SMG) to phonological processing in reading.

<table><tbody><tr><td>Magstim Rapid2 stimulator</td><td>Magstim, Carmarthenshire, UK</td><td></td><td></td></tr><tr><td>70 mm diameter figure-of-eight coil</td><td></td><td></td><td></td></tr><tr><td>Brainsight frameless stereotaxy system</td><td>RogueResearch, Montreal, Canada</td><td></td><td></td></tr><tr><td>Polaris Vicra infrared camera</td><td>Northern Digital, Waterloo, ON, Canada</td><td></td><td></td></tr></tbody></table>

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.

Figure 2 illustrates the results of two TMS experiments mentioned as examples. Namely, the first investigated whether the left SMG is causally involved in processing the sounds of words while the second investigated the temporal dynamics of this involvement. Figure 2A shows representative results of the first experiment where rTMS (10 Hz, 5 pulses, 55% of maximum intensity) was delivered to SMG during three tasks. The phonological task focused attention on the sounds of words (&#8220;Do these two words sound the same? knows-nose&#8221;) while the semantic task focused on their meaning (&#8220;Do these two words mean the same thing? idea-notion&#8221;). A third control task presented pairs of consonant letter strings and asked whether they were identical (&#8220;wsrft-wsrft&#8221;). Each task consisted of 100 trials. The results demonstrated that TMS significantly increased RTs relative to no stimulation in the phonological task by an average of 37 msec. In contrast, SMG stimulation had no significant effect on the RTs in the semantic or orthographic control tasks. In other words, a &#8220;virtual lesion&#8221; of the left SMG selectively interfered with processing the sounds of words, indicating the necessity of SMG in processing phonological aspects of written words44.
Figure 2B shows representative results of the chronometric experiment exploring the time course of phonological processing within SMG. Here, double pulse TMS was delivered at five different time windows after stimulus onset during the same phonological task with 100 trials divided into five equal blocks each testing different time window. When compared to the baseline condition (40/80 msec), a significant increase in RTs was observed when TMS was delivered 80/120, 120/160, and 160/200 msec after the onset of the stimulus. These results demonstrated SMG was engaged in phonological processing between 80 and 200 msec post-stimulus onset, indicating both early and sustained involvement in phonological processing44.
<img alt="Figure 1" src="/files/ftp_upload/51735/51735fig1highres.jpg" /> 
Figure 1.&#160;Two common methods of marking potential stimulation sites.&#160;(A)&#160;A first method involves placing a grid of markers over a hand motor area and testing each until TMS produces the expected effect. This approach is common for identifying a motor &#8220;hot spot&#8221;- that is, the place where stimulation produces the strongest, most reliable muscle contraction. (B)&#160;A second method applies additional anatomical constrains by placing a set of markers within a well-defined brain region. In this example, the location of the three markers is restricted to the anterior region of&#160;SMG. The first one is located superior to the termination of the posterior ascending ramus of the Sylvian fissure; the second one is at the ventral end of the anterior SMG; and the third one is approximately halfway between the other two sites. Stimulation markers are shown on a parasagittal plane of an individual MRI scan using frameless stereotaxy system. The black scale bar in the left bottom corner indicates a distance of 1 cm.
<img alt="Figure 2" src="/files/ftp_upload/51735/51735fig2highres.jpg" /> 
Figure 2.&#160;Reaction times (RTs) from the onset of the stimulus. (A)&#160;noTMS (light bars) and TMS (dark bars) conditions in three different language tasks. (B)&#160;Five stimulation timing conditions in the phonological task. In the example presented here, double pulses were delivered at either 40/80 msec, 80/120 msec, 120/160 msec, 160/200 msec, and 200/240 msec post stimulus onset. The first time window, 40/80 msec, was used as a baseline control condition because visual information was not expected to arrive at the SMG that rapidly. Error bars represent the standard error of the mean adjusted to correctly reflect within-subject variance50. The first experiment contains data from 12 participants and the second from 32 participants. *p &#60; 0.05.

Watch this Scientific Journal Video about Transcranial Magnetic Stimulation for Investigating Causal Brain-behavioral Relationships and their Time Course at JoVE.com

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

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 ...

transcranial-magnetic-stimulation-for-investigating-causal-brain

Research

JoVE Journal

Behavior

42.9K Views.  University College London.  Transcraniële magnetische stimulatie (TMS) is een techniek voor niet-invasief verstoren neurale verwerking van informatie en het meten van het effect ervan op gedrag. Als TMS interfereert met een taak, betekent dit dat de gestimuleerde hersengebied is noodzakelijk voor een normale taakuitvoering, zodat men hersengebieden systematisch betrekking op cognitieve functies. 

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

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 ...

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

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 ...

Extracting Visual Evoked Potentials from EEG Data Recorded During fMRI-guided Transcranial Magnetic Stimulation

Transcranial Magnetic Stimulation (TMS) is an effective method for establishing a causal link between a cortical area and cognitive/neurophysiological effects. Specifically, by creating a transient interference with the normal activity of a target region and measuring changes in an electrophysiological signal, we can establish a causal link between the stimulated brain area or network and the electrophysiological signal that we record. If target brain areas are functionally defined with prior fMRI scan, TMS could be used to link the fMRI activations with evoked potentials recorded. However, conducting such experiments presents significant technical challenges given the high amplitude artifacts introduced into the EEG signal by the magnetic pulse, and the difficulty to successfully target areas that were functionally defined by fMRI. Here we describe a methodology for combining these three common tools: TMS, EEG, and fMRI. We explain how to guide the stimulator&#39;s coil to the desired target area using anatomical or functional MRI data, how to record EEG during concurrent TMS, how to design an ERP study suitable for EEG-TMS combination and how to extract reliable ERP from the recorded data. We will provide representative results from a previously published study, in which fMRI-guided TMS was used concurrently with EEG to show that the face-selective N1 and the body-selective N1 component of the ERP are associated with distinct neural networks in extrastriate cortex. This method allows us to combine the high spatial resolution of fMRI with the high temporal resolution of TMS and EEG and therefore obtain a comprehensive understanding of the neural basis of various cognitive processes.

This paper describes a method for collecting and analyzing electroencephalography (EEG) data during concurrent transcranial magnetic stimulation (TMS) guided by activations revealed with functional magnetic resonance imaging (fMRI). A method for TMS artifact removal and extraction of event related potentials is described as well as considerations in paradigm design and experimental setup.

Transcranial Magnetic Stimulation (TMS) is an effective method for establishing a causal link between a cortical area and cognitive/neurophysiological ...

Neuroscience

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 ...

A Multimodal Imaging- and Stimulation-based Method of Evaluating Connectivity-related Brain Excitability in Patients with Epilepsy

Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations over time in the blood-oxygenation level dependent signal. rs-fcMRI has been applied extensively to identify abnormalities in brain connectivity in different neurologic and psychiatric diseases. However, the relationship among rs-fcMRI connectivity abnormalities, brain electrophysiology and disease state is unknown, in part because the causal significance of alterations in functional connectivity in disease pathophysiology has not been established. Transcranial Magnetic Stimulation (TMS) is a technique that uses electromagnetic induction to noninvasively produce focal changes in cortical activity. When combined with electroencephalography (EEG), TMS can be used to assess the brain's response to external perturbations. Here we provide a protocol for combining rs-fcMRI, TMS and EEG to assess the physiologic significance of alterations in functional connectivity in patients with neuropsychiatric disease. We provide representative results from a previously published study in which rs-fcMRI was used to identify regions with abnormal connectivity in patients with epilepsy due to a malformation of cortical development, periventricular nodular heterotopia (PNH). Stimulation in patients with epilepsy resulted in abnormal TMS-evoked EEG activity relative to stimulation of the same sites in matched healthy control patients, with an abnormal increase in the late component of the TMS-evoked potential, consistent with cortical hyperexcitability. This abnormality was specific to regions with abnormal resting-state functional connectivity. Electrical source analysis in a subject with previously recorded seizures demonstrated that the origin of the abnormal TMS-evoked activity co-localized with the seizure-onset zone, suggesting the presence of an epileptogenic circuit. These results demonstrate how rs-fcMRI, TMS and EEG can be utilized together to identify and understand the physiological significance of abnormal brain connectivity in human diseases.

Resting-state functional-connectivity MRI has identified abnormalities in patients with a wide range of neuropsychiatric disorders, including epilepsy due to malformations of cortical development. Transcranial Magnetic Stimulation in combination with EEG can demonstrate that patients with epilepsy have cortical hyperexcitability in regions with abnormal connectivity.

Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations ...

Online Transcranial Magnetic Stimulation Protocol for Measuring Cortical Physiology Associated with Response Inhibition

We describe the development of a reproducible, child-friendly motor response inhibition task suitable for online Transcranial Magnetic Stimulation (TMS) characterization of primary motor cortex (M1) excitability and inhibition. Motor response inhibition prevents unwanted actions and is abnormal in several neuropsychiatric conditions. TMS is a non-invasive technology that can quantify M1 excitability and inhibition using single- and paired-pulse protocols and can be precisely timed to study cortical physiology with high temporal resolution. We modified the original Slater-Hammel (S-H) stop signal task to create a &#34;racecar&#34; version with TMS pulses time-locked to intra-trial events. This task is self-paced, with each trial initiating after a button push to move the racecar towards the 800 ms target. GO trials require a finger-lift to stop the racecar just before this target. Interspersed randomly are STOP trials (25%) during which the dynamically adjusted stop signal prompts subjects to prevent finger-lift. For GO trials, TMS pulses were delivered at 650 ms after trial onset; whereas, for STOP trials, the TMS pulses occurred 150 ms after the stop signal. The timings of the TMS pulses were decided based on electroencephalography (EEG) studies showing event-related changes in these time ranges during stop signal tasks. This task was studied in 3 blocks at two study sites (n=38) and we recorded behavioral performance and event-related motor-evoked potentials (MEP). Regression modelling was used to analyze MEP amplitudes using age as a covariate with multiple independent variables (sex, study site, block, TMS pulse condition [single- vs. paired-pulse], trial condition [GO, successful STOP, failed STOP]). The analysis showed that TMS pulse condition (p&#60;0.0001) and its interaction with trial condition (p=0.009) were significant. Future applications for this online S-H/TMS paradigm include the addition of simultaneous EEG acquisition to measure TMS-evoked EEG potentials. A potential limitation is that in children, the TMS pulse sound could&#160;affect behavioral task performance.

We describe an experimental procedure to quantify excitability and inhibition of primary motor cortex during a motor response inhibition task by using Transcranial Magnetic Stimulation throughout the course of a Stop Signal Task.

We describe the development of a reproducible, child-friendly motor response inhibition task suitable for online Transcranial Magnetic Stimulation (TMS) ...

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 ...

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 ...

Employing Transcranial Magnetic Stimulation in a Resource Limited Environment to Establish Brain-Behavior Relationships

Neuroimaging is typically perceived as a resource demanding discipline. While this is the case in certain circumstances, institutions with limited resources have historically contributed significantly to the field of neuroscience, including neuroimaging. In the study of self-deception, we have successfully employed single-pulse TMS to determine the brain correlates of abilities including overclaiming and self-enhancement. Even without the use of neuro-navigation, methods provided here lead to successful outcomes. For example, it was discovered that decreases in self-deceptive responding lead to a decrease in affect. These methods provide data that are reliable and valid, and such methods provide research opportunities otherwise unavailable.&#160;Through the use of these methods, the overall knowledge base in the field of neuroscience is expanded, providing research opportunities to students such as those at our institution&#160;(Montclair State University is a Hispanic-Serving Institute) who are often denied such research experiences.

Transcranial Magnetic Stimulation (TMS) and low-frequency TMS (lfTMS) have&#160;been demonstrated to be major contributors to brain literature. Here we highlight the methods for investigating the cortical correlates of self-deception using TMS.

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

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