Pantelis Lioumis has been supported by an HUS VTR grant (TYH2022224), Salla Autti by the P&#228;ivikki and Sakari Sohlberg Foundation, and Hanna Renvall by the Paulo Foundation and Academy of Finland (grant 321460).

This study was approved by the Hospital District of Helsinki and Uusimaa ethics committee. Informed consent to participate was obtained before the procedure from each subject.
1. Preparation of the structural images
<ol>
	<li>Record a high-resolution T1-weighted structural MRI of the whole head for each subject (preferably with a 0 mm slice gap and 1 mm slice thickness). Acquire the images as specified in the neuronavigation system&#39;s instructions.</li>
	<li>Upload the MR images to the navigation system in its preferred format (typically DICOM or NifTI).</li>
	<li>Go through the MR images, and check for any errors (e.g., blurry cardinal points, noise disturbances, or misplacements in the 3D model reconstruction).</li>
	<li>Find the cardinal points (i.e., the middle of the ridge in each earlobe and the nasion) in the axial, sagittal, and coronal MRI planes, mark them by pressing the crosshair function in the planes, and choose the exact spot by clicking the left button of the mouse. Then, press the &#34;add landmarks&#34; button with the mouse.</li>
	<li>Insert parcellations of the brain areas of interest (e.g., pinpointed by other functional methods [MEG, fMRI, PET] or based on MRI databases or atlases)21. Choose the &#34;overlay image&#34; function.</li>
</ol>
2. Preparation for neuronavigation
<ol>
	<li>Check that the subject does not have any metal items (e.g., earrings) in the head and neck area, and ensure that there are no absolute contraindications such as intracranial metal clips.</li>
	<li>Place the subject in the patient chair. Adjust the chair so that the subject is sitting comfortably, with the neck, hands, and legs relaxed. Adjust the chair height so that the operator can comfortably stimulate the whole hemisphere under investigation.</li>
	<li>Place the head tracker so that it is stabilized during the stimulation session (with a sticker or a strap) and does not block the TMS coil from being moved freely over the head, especially over the temporal areas. The tracker may be situated slightly right on the forehead if the left hemisphere is stimulated and vice versa if the right hemisphere is stimulated to ensure that the anterior frontal lobe areas can be stimulated.</li>
	<li>Co-register the subject&#39;s head to the MRI-reconstructed 3D head model. Use a digitizing pen on the participant&#39;s head to mark the cardinal points (nasion, pre-auricular points) that were selected on the MRIs. Digitize additional points over the whole skull surface to reduce the final registration error. Place the digitizing pen over each highlighted spot on the 3D head model, and press the left pedal when the spot starts blinking on the navigator screen.</li>
	<li>Validate the registration, even if the overall error is acceptable (below 4 mm). Touch the subject&#39;s head with the tip of the digitizing pen. Double-check visually that the pen is at the analogous place on the surface of the 3D MRI-based model. If its position does not correspond to the point in the MRI, repeat steps 2.1-2.4.</li>
	<li>Ensure that both the subject and the operator wear ear protection before starting the stimulation.</li>
</ol>
3. Defining the hot spot and motor threshold for M1 stimulation
<ol>
	<li>For determining the resting motor threshold (rMT), choose a distal hand muscle (e.g., the abductor pollicis brevis [APB]) from the right hand. 
	NOTE. The motor threshold is used to define the initial stimulation intensity, which may be subsequently changed as explained below. Thus, any distal hand muscle can be used for this purpose.</li>
	<li>Place a single-use gel electrode (diameter: ~30 mm) over the right APB (the belly of the muscle), and another on the middle of the thumb (tendon). Place the ground electrode near the wrist (or follow the manufacturer&#39;s guidelines).</li>
	<li>Connect the electrodes to the electromyography (EMG)&#160;amplifier, and verify that the APB is at rest by observing the continuous EMG&#160;signal. Change the position of the hand if the recorded muscle cannot be easily relaxed.</li>
	<li>Find the cortical hot spot for determining the APB motor threshold. Starting from the motor hand knob area22, deliver a few TMS pulses, and continue by moving and rotating the coil until APB motor evoked potentials (MEPs) appear. 
	NOTE: Usually, motor representations of the thumb are located perpendicular to the lateral wall of the hand knob.
	<ol>
		<li>Choose a TMS intensity that evokes MEPs of around 200-500 &#181;V. Optimize the coil location and orientation by slightly changing its angle to evoke the maximum MEPs.</li>
	</ol>
	</li>
	<li>Save the optimal coil location in the neuronavigation software by right-clicking over the pulse number corresponding to the hot spot site and choosing the option to repeat the stimulus. Repeat the stimuli, and apply an automatic threshold hunting algorithm23 by right-clicking on the hot spot and choosing the option of motor threshold from the neuronavigation software.</li>
	<li>If these options are not available, apply the rule that a TMS pulse needs to evoke 10 MEPs (&#8805;50 &#181;V) out of 20 trials24.</li>
</ol>
4. Baseline naming of images
<ol>
	<li>Familiarize the subject with the images before the baseline object naming task11,12. Print the images (or show them in digital format), and let the subject practice before the session starts (the subject could also practice at home).
	<ol>
		<li>Use properly standardized normalized color images (e.g., from the Bank of Standardized Stimuli25; Supplementary Figure 1).</li>
		<li>Use only images that are frequently seen in an everyday environment, have a minimal number of synonyms, and have high name agreement.</li>
	</ol>
	</li>
	<li>If available, attach an accelerometer on the skin above the larynx and the vocal cords to record the speech onset, as explained in Vitikainen et al.26.</li>
	<li>Show the images to the subject one by one and ask them to name the images aloud without stimulation.
	<ol>
		<li>Present the images to the subject on a screen placed at a 0.5-1 m distance.</li>
		<li>Use a display time of 700-1,000 ms per image.</li>
	</ol>
	</li>
	<li>Adjust the inter-picture interval (IPI) to make the task slightly challenging for each subject (e.g., start with 2,500 ms, and vary between 1,500-4,000 ms).
	<ol>
		<li>If many errors occur during the baseline naming task, increase the IPI in steps of 200-300 ms. If the task is too easy, decrease the IPI in steps of 200-300 ms.</li>
	</ol>
	</li>
	<li>For the actual speech mapping session with nrTMS, omit the images that during the baseline testing were not trained adequately, not named correctly, not named clearly, not articulated correctly, named with delay or hesitance, or seemed difficult for the subject.</li>
	<li>Run the baseline naming task three times, and repeat steps 4.3-4.5 if performance is not satisfactory.</li>
</ol>
5. Speech cortical mapping
<ol>
	<li>Vary the stimulation intensity by increasing/decreasing it in steps of 1% of the stimulator&#39;s output so that each target area receives the same induced electric field (E-field), as defined for the rMT of the hand muscles at the cortical hand motor hotspot. Usually, higher intensities need to be applied for parietal than for frontotemporal targets to reach similar cortical E-fields as for the rMT hotspot.
	<ol>
		<li>Lower the intensity when stimulating cortical structures located closer to the head surface (E-field above the pre-defined rMT E-field).</li>
	</ol>
	</li>
	<li>Check before starting the stimulation that the induced E-field values are approximately similar (with a 2-3 V/m difference) in the different speech-related areas in both hemispheres.
	<ol>
		<li>Adjust the cortical depth (peeling depth) if needed.</li>
		<li>Ensure that the coil center is not in the air.</li>
	</ol>
	</li>
	<li>Start with a default picture-to-TMS interval (PTI) of 300 ms, or use a 0-400 ms PTI; a PTI above 150 ms is preferred to optimize the overlap of stimulation with language processing.</li>
	<li>Start with five pulses at a 5 Hz stimulation rate. Start from a cortical area not related to speech processing so that the subject gets used to the sensation induced by the stimulation. Then, move the coil to the expected speech-related areas.</li>
	<li>Keep the coil in the same position until the pulse train is over and the subject&#39;s naming is completed.</li>
	<li>Focus on the subject&#39;s performance as described below.
	<ol>
		<li>If no error is observed, move on to the next locus.</li>
		<li>If an error, or even a hesitation, is observed, continue stimulating that site for an additional two to three nrTMS trains, and then move on. Keep the site in mind for possible later re-stimulation.</li>
		<li>Make small coil adjustments when even a slight error is detected (e.g., minor hesitation or a louder voice during the naming due to an increased effort) to provoke clearer errors.</li>
		<li>Avoid repeating stimulation on the same site for more than five consecutive trains. Continue with other cortical sites, and revisit the site later.</li>
		<li>If repeated errors appear at several stimulated locations, lift the coil in the air above the scalp, and check if errors still occur.</li>
		<li>If errors still occur, take a break, and wait until the naming returns to normal. 
		&#8203;NOTE. Repeated naming errors unrelated to the stimulation may be common if speech-related areas are affected by a tumor or other lesion.</li>
		<li>Stimulate in blocks of 7-10 min (maximum) continuously, and have 2-5 min breaks in between. 
		NOTE: Errors become more common with long stimulations and if the subject is tired.</li>
	</ol>
	</li>
	<li>Stimulate all the possibly related anatomical areas (e.g., IFG, STG, SMG, middle temporal, precentral, postcentral, and angular gyri, and the prefrontal cortex) to obtain as many control responses as possible.</li>
	<li>If feasible and/or clinically supported, stimulate both hemispheres. Stimulate carefully inside and around the tumor region or the estimated location of the lesion even if those regions do not belong to the classical speech-related areas (for tumor and epilepsy patients).
	<ol>
		<li>Investigate cortical areas that are located away from the lesion site to identify possible spatial shifts in the language areas due to plastic changes or the mass effect, especially in patients with large lesions.</li>
	</ol>
	</li>
	<li>Reduce the TMS intensity in steps of 2%-5% of the maximum stimulator output if the mapping induces pain or discomfort.</li>
	<li>Stop the measurement if the induced pain or discomfort are not tolerated by the subject.</li>
</ol>
6. Strategy when no naming errors occur
<ol>
	<li>Terminate the stimulation, and change stimulation parameters.</li>
	<li>Decrease the IPI in steps of 200 ms from the default value (e.g., from 2,500 ms to 2,300 ms).</li>
	<li>Change the frequency of pulse delivery from 5 Hz to 7 Hz. Change the interval between the onset of the presented image and the rTMS (currently, there is no consensus on whether to increase or decrease it). Increase the stimulation intensity (without evoking discomfort).</li>
</ol>
7. Off-line analysis of the evoked naming errors
<ol>
	<li>Collaborate with an expert (e.g., a neuropsychologist), who should optimally be present in the operating room.</li>
	<li>Double-check the evoked naming errors by observing the coil positioning and possible pain interference from the video recordings.</li>
	<li>Classify the errors according to Corina et al.27 (e.g., anomia, semantic and phonological paraphasia, performance errors).
	<ol>
		<li>If a particular type of error repeats itself in the baseline video, do not consider it as an error when analyzing the stimulation session videos.</li>
	</ol>
	</li>
	<li>If an object is named after the rTMS train, consider this as a delay or a no-error; check also for possible discomfort of the subject during the pulse delivery.</li>
	<li>If the subject cannot name a given object although the tongue, lips, and jaws are moving, record a no-response error.</li>
	<li>If an image is named differently in each session, discard it.</li>
	<li>If unsure, control the performance of the neighboring stimulation site or the effect of the stimulation of the other hemisphere with the same image.</li>
</ol>

P.L. has been a consultant to Nexstim Ltd. for motor and speech cortical mapping.

Here, a protocol is presented for nrTMS SCM, which enables practically complete cortical noninvasive mapping of the most important hubs of the speech and language network. Its main advantage is that it can non-invasively simulate the DCS mapping during awake craniotomy30 or extraoperatively29 (see Figure 2). Moreover, it can be applied to language cortical network studies in healthy populations31 and in patients with diseases that are not amenable to surgery32. nrTMS for SCM may also be applied to develop neurorehabilitation strategies such as target selection (e.g., after stroke). The induction of plasticity in speech-related cortical representations by DCS prior to surgery has been studied33 to increase the extent of resection34. The possibilities of nrTMS SCM in such studies should be examined.
In the present results, a relatively large area, including classical speech-related areas and the pre-SMA, was repeatedly stimulated at three different PTIs. Each PTI showed different sensitivity and specificity to errors, but also demonstrated the well-known response variability in non-invasive brain stimulations35. Most errors were induced by the stimulation of the IFG, STG, pre-SMA, and along the frontal aslant tract36. This highlights the power of nrTMS SCM; specifically, in comparison to DCS, the stimulation can be quite flexibly targeted to several areas. We have observed that changing the PTI and recording many sessions does not clearly speed up the reaction times26,29, which would be associated with a learning effect.
The protocol highlights different parameters that can affect the accuracy of nrTMS SCM. The results can be sensitive to the choices made by the TMS operator; the present paper aims to provide a standard guideline with well-tested stimulation parameters. High specificity results from an appropriate choice of several different parameters, including the ISI, PTI, coil location, and rTMS frequency. These parameters affect the specificity of the induced errors, which reflect the functions in the underlying cortical areas; the&#160;parameter selection needs to be based on current knowledge on the neurobiology of language.
The images for the naming task should be selected so that they do not induce erroneous naming by themselves (Supplementary Figure&#160;1). Here, the images were chosen from a standardized image bank and controlled for various naming parameters25,37. For example, the pool of images was restricted to items with similar complexity and frequency in everyday use, as well as high name agreement. The choice of images can vary based on the needs of each surgical center38, the population under investigation39,&#160;the native language of the tested subject40,41 and the used task42. As presented in the protocol, the baseline image selection is finally individualized for each subject, as on-spot naming is subjective.
The stimulation frequency needs to be defined individually, because it may determine the distribution of errors during navigated transcranial magnetic brain stimulation43. The presented choice, 4-8 Hz, is based on the rTMS work by Epstein et al.44. The initial stimulation frequency is set to 5 Hz. If no errors are detected, the stimulation frequency is increased to 7 Hz. Higher frequencies may reduce nrTMS-induced pain and increase the specificity of naming errors45. Higher frequencies also have the advantage of limiting the pulses to a short and more specific time interval. They may, however, affect functions related to, for example, speech motor execution44,46, which are not the main target of the present protocol.
It is recommended to vary the PTI between 150-400 ms. This is an important time window for word retrieval during the object naming task28,47. The protocol aims at speech specificity by avoiding the interference of basic visual processing, which occurs during the first 150 ms after image presentation and may affect object naming but is unrelated to speech production. The recommended upper limit for the PTI is based on typical response latencies in picture naming in the same subject28,48, and individual variation in the optimal values between subjects can be expected (see Figure 1). The PTI selection should ideally be based on personalized measures, although this may be logistically demanding in a clinical setting. Helsinki University Hospital protocols usually start with a 300 ms PTI. It may also be useful to change the PTI based on the stimulated area12,13,49, as indicated by several language studies28,47,50. Nevertheless, PTIs outside the above-mentioned window may also induce naming errors that are useful for presurgical evaluation (for a comparative study, see Krieg et al.49 using PTIs of 0-300 ms).
The cortical speech network is widespread and varies among individuals, particularly in patients with tumors and epilepsy29,30,39. nrTMS induces language disturbance with great variability across individuals, analogous to those observed during awake craniotomy stimulations27,51. The information obtained from fMRI50, DTI52,53,54, and MEG55 can direct the nTMS user and result in a procedure that is tailored for each individual and is, thus, more specific and accurate. The objective in nrTMS SCM is to increase the specificity, reduce the number of non-responders, guide the DCS reliably, or replace it when the resources and conditions do not allow a team of highly specialized experts to perform it.&#160;In the future, multilocus TMS (mTMS) could be applied in the procedure to stimulate different parts of the cortex without physically moving the stimulation coil56.
The present protocol can be performed with several types of naming tasks42,57 or other cognitive tasks (calculations, decision making, etc.)58. The video recording can disclose crucial features of the task performance (e.g., grimaces by the subject indicating that no motor speech arrest is induced) that can go unobserved during the stimulation. The setup also allows for asking the subject about the nrTMS-induced experiences and sensations by jointly viewing the video recording. This can help in distinguishing pain-induced errors from the true effects of nrTMS. Finally, the protocol can be easily modified to different subject groups (e.g., bilingual individuals31) and to serve the needs of each surgical or research team.

During neurosurgery due to cerebral disease (e.g., epilepsy or a tumor), the extent of resection must be optimized to preserve brain regions that support critical functions. Areas vital for patient integrity and quality of life, such as language-related ones, should be characterized prior to the removal of brain tissue. Typically, they cannot be individually identified merely based on anatomical landmarks1. The functional mapping of language areas for surgical decision-making is usually done invasively by electrical direct cortical stimulation (DCS), which enables the neurosurgeon to understand the organization of the crucial cortical and subcortical structures within each patient2. Although DCS during awake surgery is considered the gold&#160;standard of cortical mapping for speech functions, it is limited by its invasiveness, methodological challenges, and the high stress it induces for both the patient and the surgical team. This protocol describes non-invasive speech cortical mapping (SCM) using navigated transcranial magnetic stimulation (navigated TMS or nTMS). Accurate non-invasive mapping aids in surgical planning, and reduces the time, costs, and risks in the operation room (OR). It also provides an alternative for those patients who are not suitable for awake craniotomy3.
Non-invasive imaging methods have already greatly benefited presurgical planning. Anatomical magnetic resonance imaging (MRI) is crucial for locating tumors and brain lesions; in neuronavigation4 and in the navigated TMS mapping5, it guides the operator to the cortical sites of interest. Diffusion-based MRI (dMRI) tractography provides detailed information on the white-matter fiber tracts that connect cortical regions5,6. During the last decade, functional imaging techniques, most notably functional MRI (fMRI) and magnetoencephalography (MEG), have been increasingly used for preoperative motor and speech cortical mapping (SCM)2,8,9. Each method brings benefits to the preoperative mapping procedure, and can, for example, provide information on the functionally related regions outside of the conventional language areas (Broca&#39;s and Wernicke&#39;s areas). fMRI has been the most commonly used method1 due to its high availability; it has been compared to DCS in the localization of speech-related areas with variable results2,10. However, although functional imaging can identify the involved brain regions, it cannot determine whether these regions are critical for the function to be preserved.
Navigated repetitive TMS (nrTMS) is nowadays used as an alternative to the aforementioned methods for preoperative non-invasive SCM11,12. nrTMS SCM is especially efficient in identifying speech-related cortical areas within the inferior frontal gyrus (IFG), superior temporal gyrus (STG), and supramarginal gyrus (SMG)11,13. An advantage of the method is that the offline analysis of the errors evoked by the stimulation allows the analyzer to be unaware of the stimulation site. It is, thus, possible to judge the error without a priori information of the cortical site&#39;s relevance to the speech network. This is enabled by a video recording, which allows the analyzer to distinguish subtle differences in errors, such as semantic and phonological paraphasia, more reliably than during the actual examination11,12. The nrTMS SCM approach currently surpasses the performance of MEG or fMRI speech mapping alone10,14, and additional functional or anatomical information may be used to fine-tune the nrTMS procedure. Preoperative mapping with nrTMS has been demonstrated to shorten operation times and reduce the required size of craniotomy and damage to the eloquent cortex15. It shortens the time of hospitalization and enables a more extensive removal of tumor tissue, thereby increasing patient survival rates15. nrTMS has been validated against intraoperative DCS mapping; specifically, the sensitivity of nrTMS in SCM is high, but its specificity remains low, with excessive false positives compared to DCS13,16.
Currently, presurgical non-invasive SCM with nrTMS can assist in patient selection for operation, help in designing the surgery, and speed up the DCS conducted during the surgery17. Here, a detailed description of how nrTMS SCM can be performed to obtain reliable speech-specific results is provided. After gaining practical experience, the suggested protocol can be tailored to best fit the patient- and site-specific demands. The protocol can be further expanded to certain targets, such as speech production (speech arrest)18,19 or visual and cognitive functions20.

<table><tbody><tr><td>Neurology surface electrodes</td><td>Ambu A/S</td><td>Ambu Neuroline Ground</td><td></td></tr><tr><td>Neurology surface electrodes</td><td>Ambu A/S</td><td>Ambu Neuroline 720</td><td></td></tr><tr><td>Off-line speech error analyzer</td><td>Nexstim Ltd</td><td>NexSpeech 2.1.0</td><td></td></tr><tr><td>Single patient surface electrode</td><td>Ambu A/S</td><td>Ambu Neuroline 700</td><td></td></tr><tr><td>Stimulator</td><td>Nexstim Ltd</td><td>NBS 4.3</td><td></td></tr></tbody></table>

study design for navigated repetitive transcranial magnetic stimulation for speech cortical mapping

The cortical areas involved in human speech should be characterized reliably prior to surgery for brain tumors or drug-resistant epilepsy. The functional mapping of language areas for surgical decision-making is usually done invasively by electrical direct cortical stimulation (DCS), which is used to identify the organization of the crucial cortical and subcortical structures within each patient. Accurate preoperative non-invasive mapping aids surgical planning, reduces time, costs, and risks in the operating room, and provides an alternative for patients not suitable for awake craniotomy. Non-invasive imaging methods like MRI, fMRI, MEG, and PET are currently applied in presurgical design and planning. Although anatomical and functional imaging can identify the brain regions involved in speech, they cannot determine whether these regions are critical for speech. Transcranial magnetic stimulation (TMS) non-invasively excites the cortical neuronal populations by means of electric field induction in the brain. When applied in its repetitive mode (rTMS) to stimulate a speech-related cortical site, it can produce speech-related errors analogous to those induced by intraoperative DCS. rTMS combined with neuronavigation (nrTMS) enables neurosurgeons to preoperatively assess where these errors occur and to plan the DCS and the operation to preserve the language function. A detailed protocol is provided here for non-invasive speech cortical mapping (SCM) using nrTMS. The proposed protocol can be modified to best fit the patient- and site-specific demands. It can also be applied to language cortical network studies in healthy subjects or in patients with diseases that are not amenable to surgery.

A navigated transcranial magnetic stimulation system with integrated screens and cameras was used. Figure 1A-C highlights the different TMS-evoked naming errors in one subject during the task at different PTIs (180 ms, 200 ms, and 215 ms). The effect of the timing of the TMS pulses on the number of errors evoked is evident. In other words, TMS-related changes in performance were detected in different areas at different PTIs. The number of errors varied depending on the timing of the TMS pulses even at the same cortical sites, in accordance with MEG studies demonstrating the variation in the timing of activation in different speech-related cortical areas28. A comparison of the results between extraoperative DCS mapping and nrTMS with a fixed PTI at 300 ms in a patient with intractable epilepsy is shown in Figure 2. The data were obtained from a previous publication focusing on epilepsy29.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/64492/64492fig01.jpg" /> 
Figure 1: Results of an nrTMS SCM illustrated over a 3D MRI-based model from a healthy volunteer. (A) PTI of 180 ms. (B) PTI of 200 ms. (C) PTI of 215ms. In addition to the major speech-related areas, the pre-supplementary motor area (pre-SMA) was stimulated as described in the protocol (step 5.7). Most of the errors were evoked in the classical speech areas (IFG, STG, SMG), but also along the path connecting the pre-SMA and Broca&#39;s area (the close-to-midline green spots in A and B). <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/64492/64492fig01large.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/64492/64492fig02.jpg" /> 
Figure 2: Comparison of the results between extraoperative DCS mapping and nrTMS with a fixed PTI at 300 ms in a patient with intractable epilepsy. (A)&#160;Extraoperative grid mapping at the age of 13. The yellow spheres represent all the electrodes on the cortex. The sites of electrode stimulation (2-5 mA) that induced motor responses of the hand and mouth (green circles), naming arrest (anomia; red circles), and interrupting sentence repetition (pink circles) are shown. (B)&#160;nrTMS SCM of the same patient at the age of 15. The sites of nrTMS-induced anomias (red dots), semantic and phonological paraphasias (yellow dots), and hesitations (white dots) are shown. The areas with highly reproducible and reliable error induction are circled. The data for this image were taken from the study of Lehtinen et al.29. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/64492/64492fig02large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
Supplementary Figure 1:&#160;Examples of images presented in the nrTMS SCM experiment (in Finnish in parentheses). (A) Hanger (Henkari). (B) Scissors (Sakset). (C) Strawberry (Mansikka). <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/64492/supplemfigure1.jpg" target="_blank">Please click here to download this File.</a>

Watch this Scientific Journal Video about Study Design for Navigated Repetitive Transcranial Magnetic Stimulation for Speech Cortical Mapping at JoVE.com

Study Design for Navigated Repetitive Transcranial Magnetic Stimulation for Speech Cortical Mapping

Navigated repetitive transcranial magnetic stimulation is a highly efficient non-invasive tool for mapping speech-related cortical areas. It helps in designing brain surgery and speeds up the direct cortical stimulation conducted during the surgery. This report describes how to perform speech cortical mapping reliably for preoperative evaluation and research.

The cortical areas involved in human speech should be characterized reliably prior to surgery for brain tumors or drug-resistant epilepsy. The functional ...

study-design-for-navigated-repetitive-transcranial-magnetic

Nanyang Technological University

Research

JoVE Journal

Medicine

1.4K Views.  Aalto University School of Science. Ons protocol is niet-invasief en vergelijkbaar met de invasieve gouden standaard. Het kan dus helpen bij het selecteren van patiënten bij het ontwerpen van de operatie en de directe corticale stimulatie tijdens de operatie versnellen. Deze techniek maakt gedetailleerde spraakcorticale mapping en flexibele veranderingen van de taak en de stimulatieparameters mogelijk.Het kan ook worden toegepast op een gezonde populatie en worden aangepast voor elke vorm van taaltaak. Ons protocol kan ...

Video: Study Design for Navigated Repetitive Transcranial Magnetic Stimulation for Speech Cortical Mapping

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 ...

Behavior

Neuronavigation-guided Repetitive Transcranial Magnetic Stimulation for Aphasia

Repetitive transcranial magnetic stimulation (rTMS) is widely used for several neurological conditions, as it has gained acknowledgement for its potential therapeutic effects. Brain excitability is non-invasively modulated by rTMS, and rTMS to the language areas has proved its potential effects on treatment of aphasia. In our protocol, we aim to artificially induce virtual aphasia in healthy subjects by inhibiting Brodmann area 44 and 45 using neuronavigational TMS (nTMS), and F3 of the International 10-20 EEG system for conventional TMS (cTMS). To measure the degree of aphasia, changes in reaction time to a picture naming task pre- and post-stimulation are measured and compare the delay in reaction time between nTMS and cTMS. Accuracy of the two TMS stimulation methods is compared by averaging the Talairach coordinates of the target and the actual stimulation. Consistency of stimulation is demonstrated by the error range from the target. The purpose of this study is to demonstrate use of nTMS and to describe the benefits and limitations of the nTMS compared to those of cTMS.

This study is designed to test the hypothesis that neuronavigational system-guided transcranial magnetic stimulation has higher accuracy for targeting the intended target as demonstrated by eliciting a greater degree of virtual aphasia in healthy subjects, measured by delay in reaction time to picture naming.

Repetitive transcranial magnetic stimulation (rTMS) is widely used for several neurological conditions, as it has gained acknowledgement for its potential ...

Utilizing Repetitive Transcranial Magnetic Stimulation to Improve Language Function in Stroke Patients with Chronic Non-fluent Aphasia

Transcranial magnetic stimulation (TMS) has been shown to significantly improve language function in patients with non-fluent aphasia1. In this experiment, we demonstrate the administration of low-frequency repetitive TMS (rTMS) to an optimal stimulation site in the right hemisphere in patients with chronic non-fluent aphasia. A battery of standardized language measures is administered in order to assess baseline performance. Patients are subsequently randomized to either receive real rTMS or initial sham stimulation. Patients in the real stimulation undergo a site-finding phase, comprised of a series of six rTMS sessions administered over five days; stimulation is delivered to a different site in the right frontal lobe during each of these sessions. Each site-finding session consists of 600 pulses of 1 Hz rTMS, preceded and followed by a picture-naming task. By comparing the degree of transient change in naming ability elicited by stimulation of candidate sites, we are able to locate the area of optimal response for each individual patient. We then administer rTMS to this site during the treatment phase. During treatment, patients undergo a total of ten days of stimulation over the span of two weeks; each session is comprised of 20 min of 1 Hz rTMS delivered at 90% resting motor threshold. Stimulation is paired with an fMRI-naming task on the first and last days of treatment. After the treatment phase is complete, the language battery obtained at baseline is repeated two and six months following stimulation in order to identify rTMS-induced changes in performance. The fMRI-naming task is also repeated two and six months following treatment. Patients who are randomized to the sham arm of the study undergo sham site-finding, sham treatment, fMRI-naming studies, and repeat language testing two months after completing sham treatment. Sham patients then cross over into the real stimulation arm, completing real site-finding, real treatment, fMRI, and two- and six-month post-stimulation language testing.

We explore the use of repetitive transcranial magnetic stimulation (rTMS) to improve language abilities in patients with chronic stroke and non-fluent aphasia. After identifying a site in the right frontal gyrus for each patient that responds optimally to stimulation, we target this site during ten days of rTMS treatment.

Transcranial magnetic stimulation (TMS) has been shown to significantly improve language function in patients with non-fluent aphasia1. In this ...

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

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 ...

Mapping the After-effects of Theta Burst Stimulation on the Human Auditory Cortex with Functional Imaging

Auditory cortex pertains to the processing of sound, which is at the basis of speech or music-related processing1. However, despite considerable recent progress, the functional properties and lateralization of the human auditory cortex are far from being fully understood. Transcranial Magnetic Stimulation (TMS) is a non-invasive technique that can transiently or lastingly modulate cortical excitability via the application of localized magnetic field pulses, and represents a unique method of exploring plasticity and connectivity. It has only recently begun to be applied to understand auditory cortical function 2. 
An important issue in using TMS is that the physiological consequences of the stimulation are difficult to establish. Although many TMS studies make the implicit assumption that the area targeted by the coil is the area affected, this need not be the case, particularly for complex cognitive functions which depend on interactions across many brain regions 3. One solution to this problem is to combine TMS with functional Magnetic resonance imaging (fMRI). The idea here is that fMRI will provide an index of changes in brain activity associated with TMS. Thus, fMRI would give an independent means of assessing which areas are affected by TMS and how they are modulated 4. In addition, fMRI allows the assessment of functional connectivity, which represents a measure of the temporal coupling between distant regions. It can thus be useful not only to measure the net activity modulation induced by TMS in given locations, but also the degree to which the network properties are affected by TMS, via any observed changes in functional connectivity.
Different approaches exist to combine TMS and functional imaging according to the temporal order of the methods. Functional MRI can be applied before, during, after, or both before and after TMS. Recently, some studies interleaved TMS and fMRI in order to provide online mapping of the functional changes induced by TMS 5-7. However, this online combination has many technical problems, including the static artifacts resulting from the presence of the TMS coil in the scanner room, or the effects of TMS pulses on the process of MR image formation. But more importantly, the loud acoustic noise induced by TMS (increased compared with standard use because of the resonance of the scanner bore) and the increased TMS coil vibrations (caused by the strong mechanical forces due to the static magnetic field of the MR scanner) constitute a crucial problem when studying auditory processing. 
This is one reason why fMRI was carried out before and after TMS in the present study. Similar approaches have been used to target the motor cortex 8,9, premotor cortex 10, primary somatosensory cortex 11,12 and language-related areas 13, but so far no combined TMS-fMRI study has investigated the auditory cortex. The purpose of this article is to provide details concerning the protocol and considerations necessary to successfully combine these two neuroscientific tools to investigate auditory processing. 
Previously we showed that repetitive TMS (rTMS) at high and low frequencies (resp. 10 Hz and 1 Hz) applied over the auditory cortex modulated response time (RT) in a melody discrimination task 2. We also showed that RT modulation was correlated with functional connectivity in the auditory network assessed using fMRI: the higher the functional connectivity between left and right auditory cortices during task performance, the higher the facilitatory effect (i.e. decreased RT) observed with rTMS. However those findings were mainly correlational, as fMRI was performed before rTMS. Here, fMRI was carried out before and immediately after TMS to provide direct measures of the functional organization of the auditory cortex, and more specifically of the plastic reorganization of the auditory neural network occurring after the neural intervention provided by TMS. 
Combined fMRI and TMS applied over the auditory cortex should enable a better understanding of brain mechanisms of auditory processing, providing physiological information about functional effects of TMS. This knowledge could be useful for many cognitive neuroscience applications, as well as for optimizing therapeutic applications of TMS, particularly in auditory-related disorders.

Auditory processing is the basis of speech and music-related processing. Transcranial Magnetic Stimulation (TMS) has been used successfully to study cognitive, sensory and motor systems but has rarely been applied to audition. Here we investigated TMS combined with functional Magnetic Resonance Imaging to understand the functional organization of auditory cortex.

Auditory cortex pertains to the processing of sound, which is at the basis of speech or music-related processing1. However, despite considerable recent ...

Biology

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 ...

Bilateral Assessment of the Corticospinal Pathways of the Ankle Muscles Using Navigated Transcranial Magnetic Stimulation

Distal leg muscles receive neural input from motor cortical areas via the corticospinal tract, which is one of the main motor descending pathway in humans and can be assessed using transcranial magnetic stimulation (TMS). Given the role of distal leg muscles in upright postural and dynamic tasks, such as walking, a growing research interest in the assessment and modulation of the corticospinal tracts relative to the function of these muscles has emerged in the last decade. However, methodological parameters used in previous work have varied across studies making the interpretation of results from cross-sectional and longitudinal studies less robust. Therefore, use of a standardized TMS protocol specific to the assessment of leg muscles&#39; corticomotor response (CMR) will allow for direct comparison of results across studies and cohorts. The objective of this paper is to present a protocol that provides the flexibility to simultaneously assess the bilateral CMR of two main ankle antagonistic muscles, the tibialis anterior and soleus, using single pulse TMS with a neuronavigation system. The present protocol is applicable while the examined muscle is either fully relaxed or isometrically contracted at a defined percentage of maximum isometric voluntary contraction. Using each subject&#39;s structural MRI with the neuronavigation system ensures accurate and precise positioning of the coil over the leg cortical representations during assessment. Given the inconsistency in CMR derived measures, this protocol also describes a standardized calculation of these measures using automated algorithms. Though this protocol is not conducted during upright postural or dynamic tasks, it&#160;can be used to assess bilaterally any pair of leg muscles, either antagonistic or synergistic, in both neurologically intact and impaired subjects.

The present protocol describes the simultaneous, bilateral assessment of the corticomotor response of the tibialis anterior and soleus during rest and tonic voluntary activation using a single pulse transcranial magnetic stimulation and neuronavigation system.

Distal leg muscles receive neural input from motor cortical areas via the corticospinal tract, which is one of the main motor descending pathway in humans ...

Non-Invasive Modulation and Robotic Mapping of Motor Cortex in the Developing Brain

Mapping the motor cortex with transcranial magnetic stimulation (TMS) has potential to interrogate motor cortex physiology and plasticity but carries unique challenges in children. Similarly, transcranial direct current stimulation (tDCS) can improve motor learning in adults but has only recently been applied to children. The use of tDCS and emerging techniques like high&#8211;definition tDCS (HD-tDCS) require special methodological considerations in the developing brain. Robotic TMS motor mapping may confer unique advantages for mapping, particularly in the developing brain. Here, we aim to provide a practical, standardized approach for two integrated methods capable of simultaneously exploring motor cortex modulation and motor maps in children. First, we describe a protocol for robotic TMS motor mapping. Individualized, MRI-navigated 12x12 grids centered on the motor cortex guide a robot to administer single-pulse TMS. Mean motor evoked potential (MEP) amplitudes per grid point are used to generate 3D motor maps of individual hand muscles with outcomes including map area, volume, and center of gravity. Tools to measure safety and tolerability of both methods are also included. Second, we describe the application of both tDCS and HD-tDCS to modulate the motor cortex and motor learning. An experimental training paradigm and sample results are described. These methods will advance the application of non-invasive brain stimulation in children.

We demonstrate protocols for the modulation (tDCS, HD-tDCS) and mapping (robotic TMS) of the motor cortex in children.

Mapping the motor cortex with transcranial magnetic stimulation (TMS) has potential to interrogate motor cortex physiology and plasticity but carries ...

Neuronavigated tDCS for Enhanced Electrode Placement Accuracy in fMRI Studies

Neuronavigated Focalized Transcranial Direct Current Stimulation Administered During Functional Magnetic Resonance Imaging

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that allows the modulation of the excitability and plasticity of the human brain. Focalized tDCS setups use specific electrode arrangements to constrain the current flow to circumscribed brain regions. However, the effectiveness of focalized tDCS can be compromised by electrode positioning errors on the scalp, resulting in significant reductions of the current dose reaching the target brain regions for tDCS. Electrode placement guided by neuronavigation based on the individual&#39;s head and brain anatomy derived from structural magnetic resonance imaging (MRI) data may be suited to improve positioning accuracy.
This protocol describes the method of neuronavigated electrode placement for a focalized tDCS setup, which is suitable for concurrent administration during functional MRI (fMRI). We also quantify the accuracy of electrode placement and investigate electrode drift in a concurrent tDCS-fMRI experiment. Critical steps involve the optimization of electrode positions based on current modeling that considers the individual&#39;s head and brain anatomy, the implementation of neuronavigated electrode placement on the scalp, and the administration of optimized and focal tDCS during fMRI.
The regional precision of electrode placement is quantified using the Euclidean norm (L2&#160;Norm) to determine deviations of the actual from the intended electrode positions during a concurrent tDCS-fMRI study. Any potential displacement of electrodes (drift) during the experiment is investigated by comparing actual electrode positions before and after the fMRI acquisition. In addition, we directly compare the placement accuracy of neuronavigated tDCS to that achieved by a scalp-based targeting approach (a 10-20 Electroencephalography (EEG) system). These analyses demonstrate superior placement accuracy for neuronavigation compared to scalp-based electrode placement and negligible electrode drift across a 20 min scanning period.

This protocol describes the method of neuronavigated electrode placement for focal, transcranial direct current stimulation (tDCS) administered during functional magnetic resonance imaging (fMRI).

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that allows the modulation of the excitability and plasticity ...

Study Design for Navigated Repetitive Transcranial Magnetic Stimulation for Speech Cortical Mapping

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