This study was supported by a grant (A101901) from the Korea Healthcare Technology R&#38;D Project, Ministry of Health &#38; Welfare, Republic of Korea. We thank Dr Ji-Young Lee for providing technical assistance throughout the procedure.

Ethics statement: This study was approved by the institutional review board of a blinded hospital.
1. Preparing Materials (Table 1)
<ol>
	<li>Use TMS equipment with maximum output of 3.0 Tesla and a power supply of 200-240 Vac 50/60 Hz 5A at a pulse width of 350 &#181;sec.</li>
	<li>Acquire resting motor threshold (RMT) in each subject by electromyography (EMG) to determine the motor evoked potential (MEP) using the TMS system and the active electrode (see step 3.1 for details). Set the RMT as individual intensity for the actual TMS study protocol (Figure 1). 
	Note: The neuronavigational system includes a computer screen, subjective tracker, coil tracker, pointer, calibration block, camera, and TMS chair seating system. (Figures 2-4)</li>
	<li>Use the Superlab program to set up the picture naming task and present the stimulus to the subjects to test the degree of induced virtual aphasia.</li>
	<li>Record reaction time for each picture using a voice recording system, described in more detail in step 4.</li>
	<li>Analyze latency and duration of the picture naming response by a voice analysis system, described in more detail in step 4.</li>
</ol>
2. Checking the Study Design
<ol>
	<li>Use rTMS to Induce Virtual Aphasia.
	<ol>
		<li>Ask the subject to perform the picture naming task, described in more detail in step 4. Picture naming task.</li>
		<li>Apply either neuronavigation-guided rTMS (nTMS) or conventional rTMS (cTMS) during the picture naming task. The details of cTMS are described in steps 5.3.2 and 5.5.</li>
	</ol>
	</li>
	<li>Measure reaction time and error rate for picture naming and compare the results under both conditions, as described in more detail in step 4.</li>
</ol>
3. Preparation of the TMS Protocol
<ol>
	<li>Determine RMT
	<ol>
		<li>Place the active electrode on the left first dorsal interosseous (FDI) muscle.</li>
		<li>Deliver 10 consecutive stimulations to the right M1 area at a 4-6 sec interstimulus interval, checking the contraction of the left FDI muscle.</li>
		<li>Determine subject&#39;s RMT using the minimum TMS intensity at which a peak-to-peak MEP amplitude greater than 50 uV is produced at least five times.</li>
	</ol>
	</li>
	<li>TMS Mapping
	<ol>
		<li>Obtain a high resolution T1-weighted magnetic resonance (MR) anatomical images using a 3-T MR scanner of the subject for use of the neuronavigational system. The parameters for the MRI scan are summarized in Table 1. 
		Note: Transfer the brain MR images to the neuronavigation program, which reconstructs the brain curvilinear and skin of each individual using anatomical guidance of the anterior commissure (AC) and posterior commissure (PC), as shown in Figure 5.
		<ol>
			<li>Reconstruct the skin structure
			<ol>
				<li>Obtain the file of the subject&#39;s brain MR image in standard Digital Imaging and Communications in Medicine (DICOM). format. Convert the MR image by selecting &#34;convert study&#34;. Set the search directory from which the file is transferred to the neuronavigation computer. Convert type should be selected by DICOM type to be used in the neuronavigation program.</li>
				<li>Transfer the DICOM file to the computer in which the neuronavigation program is installed. Implement the navigation program. The default icon is &#34;Anatomical.&#34; For a new patient record, select one of the DICOM image files.</li>
				<li>Click &#34;Atlas spaces&#34;. This step is to set the reference point to reconstruct each image. Press &#34;new&#34; in the dropbox and set the reference anatomical structure by clicking&#34; manual (AC-PC box)&#34;.</li>
				<li>Find the patient&#39;s AC of the corpus callosum, just the midline of two hemispheres placed in front of the columns of the fornix. Mark AC on the MR image and click &#34;set AC&#34;.</li>
				<li>Find the patient&#39;s PC, the midline of the two hemispheres in the dorsal aspect of the upper end of the cerebral aqueduct. Mark PC on the MR image and click &#34;set PC&#34;.</li>
				<li>Click &#34;Reconstructions&#34; to make the skin structure. Press &#34;new&#34; in the dropbox to select &#34;Skin&#34;. Set the range for reconstruction on the MR images. Be sure to include the whole skull with the nasal tip and both ears.</li>
				<li>Click &#34;compute skin&#34; in the new structure. Wait until the process is done. After completion of skin construction, skin morphology should be displayed.</li>
			</ol>
			</li>
			<li>Select &#34;Full brain curvilinear&#34; in the &#34;Reconstruction&#34; section to reconstruct the brain curvilinear following 3.2.1.1. Similar to the previous step, set the range for reconstruction on the MR images containing the nasal tip. Click &#34;compute curvilinear&#34;. Full brain curvilinear should be displayed after construction is completed.</li>
		</ol>
		</li>
		<li>Mark the nasion, nasal tip, and both tragus to register the anatomical landmarks. This step is to match the anatomical point between the patient and the reconstructed skin structure for configuration of the relative position of the target on the brain cortex (Figure 6).
		<ol>
			<li>Click the &#34;Landmark&#34; icon. To configure the landmark, mark the nasion (point between the forehead nose, at the junction of the nasal bones) on the computed skin structure. Register it by clicking &#34;new&#34; and store it as &#34;Landmark 1&#34;</li>
			<li>Mark the nasal tip after registering nasion as landmark 1. Register the nasal tip by clicking &#34; new&#34; and store it as &#34;Landmark 2&#34;</li>
			<li>Mark each tragus on the skin structure. The tragus is the small pointed eminence of the external ear, situated in front of the concha. Register each tragus after marking and clicking &#34;new&#34; landmarks. For this protocol, the right tragus is registered as &#34;Landmark 3&#34; and the left is registered as &#34;Landmark 4&#34;.</li>
		</ol>
		</li>
		<li>Put the head strap with the subjective tracker on the participant&#39;s head. Calibrate the coil tracker with the calibration block of the navigational seating system at every session for each subject. Make sure the navigational camera detects and displays all of the tracking system of the subject, the chair, the coil, and the pointer on the computer screen before proceeding.
		<ol>
			<li>Calibrating the coil with the seating system.
			<ol>
				<li>Calibrate the coil tracker before every nTMS stimulation. At the main computer menu, select &#34;Window&#34;. Click &#34;TMS coil calibration&#34; in the dropbox. Click &#34;new calibrate&#34;. At the second session, select the coil name used the first time and click &#34;Re-calibrate&#34;.</li>
				<li>Place the TMS coil on the standard point posterior of calibration block. Be sure the coil is horizontally placed. Check that the camera is detecting both the calibration block and coil tracker (shown in green). Then, click &#34;Begin calibration countdown&#34;, and a 5 sec of countdown will start. Hold the coil still during the countdown.</li>
			</ol>
			</li>
		</ol>
		</li>
	</ol>
	</li>
</ol>
4. Picture Naming Task
<ol>
	<li>Set the picture naming program to present each stimulus for 3,000 msec before automatically moving onto the next picture.</li>
	<li>Ask the participant to name the presented picture as accurately and quickly as possible.</li>
	<li>Measure reaction time (latency from pop up of the stimulus on the screen to the first sound made by the participant) for each picture by detecting the sound made by the subject through the headset microphone using the freeware voice analysis program.
	<ol>
		<li>Forty pictures matched in name length and segments of two to three from the picture database of the Korean version of the Boston Naming Test (K-BNT) are presented on the screen pre- and post stimulation, as in the study by Kim et al., (2014).</li>
	</ol>
	</li>
</ol>
5. TMS Mapping Protocol
<ol>
	<li>Deliver1 Hz stimulation at an intensity of 90% of RMT for 10 min, with a total of 600 TMS pulses.</li>
	<li>Hold the figure-eight coil tangentially to the skull with the coil perpendicularly oriented to the target.</li>
	<li>TMS Mapping (Figure 7)
	<ol>
		<li>Identify the anatomical inferior frontal gyrus (IFG) based on the surface of the normalized brain, for nTMS.
		<ol>
			<li>Register the IFG as the nTMS target.
			<ol>
				<li>Click &#34;Target&#34; and press &#34;Configure targets&#34;. Mark the IFG on the window displaying the brain curvilinear. Detailed target setting is achieved by targeting each transverse and sagittal MR images. Save the point as &#34;Trajectory&#34;.</li>
			</ol>
			</li>
			<li>Register landmarks with the subjects scalp.
			<ol>
				<li>Click &#34;Sessions&#34; for mapping. Create a new session by selecting &#34;Online session&#34; in the new dropbox. A &#34;Session 1&#34; window is created, within which the default icon is &#34;Targets&#34;. Select the target name saved in step 3.2.2.2. (Select &#34;Trajectory 1&#34;). Click the &#34;Add&#34; button, and move to the next step.</li>
				<li>Click &#34;Registration&#34;. This step is to match the reconstructed brain curvilinear with the subject. The registered landmark in step 3.2.2.1. is used for matching the anatomical point with the real anatomical structure.</li>
				<li>Make sure the camera identifies both the pointer and the subject tracker, displayed in green color. Point to the subject&#39;s nasion with the pointer. Click &#34;Sample % Go to Next Landmark&#34;. Point to the subject&#39;s nasal tip and sample it. Repeat until all four landmarks are matched.</li>
			</ol>
			</li>
		</ol>
		</li>
		<li>Place the coil on F3 of the 10-20 international EEG system7 for cTMS.</li>
	</ol>
	</li>
	<li>Look at the screen to ensure the coil is on the desired target and is maintained throughout the nTMS procedure. The screen should display the subject&#39;s brain surface, intended target, and the coil, as well as the error range as the coil moves away from the target shown by the bull&#39;s eye (Figure 8). Referring to the screen, the operator adjusts the coil on the target as it is moved away.
	<ol>
		<li>Perform nTMS over the registered target
		<ol>
			<li>Click &#34;Perform&#34; on the screen after registering the subject&#39;s landmarks as described in step 5.3.1.1. To change the default setting of the camera to detect the pointer, choose the coil name saved during step 3.2.3.1. at the bottom of the &#34;Driver&#34; dropbox. Make sure the camera identifies both the subject tracker and coil tracker.</li>
			<li>Check that the screen displays the relative distance and angle of the TMS coil from the registered target (IFG). If the coil moves away from the target, the distance is marked in red, whereas it is marked in green when the coil is within the intended target range. Try to obtain the angle between the coil and the target as a bull&#39;s eye as much as possible.</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>Turn the screen away from the operator for the cTMS procedure to blindly deliver the TMS. The coil is maintained as it was at the beginning of the session.</li>
</ol>
6. Topograhic Data Acquisition
<ol>
	<li>Record coil location per stimulation by manually pressing the &#34; record&#34; button on the remote control.</li>
	<li>Upon recording each stimulation, acquires Taliarach coordinates in the x, y, z for the designated target and actual stimulated area.</li>
	<li>Depict the coordinates on a single normalized brain using the freeware image processing program (MRIcro, http://www.mccauslandcenter.sc.edu/mricro/mricro/index.html).</li>
	<li>Acquire corresponding anatomical brain areas, including the Brodmann area, the gyrus, lobe, and hemisphere region labels to the talairach coordinates using a freeware labeling program (Talairachclient,&#160;http://www.talairach.org/client.html).</li>
</ol>

<ol><li>Barker, A. T., Jalinous, R., Freeston, I. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Non-invasive+magnetic+stimulation+of+human+motor+cortex%5BTitle%5D)+AND+%22Lancet%22%5BJournal%5D)">Non-invasive magnetic stimulation of human motor cortex.</a> Lancet. 11 (1), 1106-1107 (1985).</li>
<li>Pape, T. L., Rosenow, J., Lewis, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Transcranial+magnetic+stimulation%3A+a+possible+treatment+for+TBI%5BTitle%5D)+AND+%22J+Head+Trauma+Rehabil%22%5BJournal%5D)">Transcranial magnetic stimulation: a possible treatment for TBI.</a> J Head Trauma Rehabil. 21 (5), 437-451 (2006).</li>
<li>Ruohonen, J., Karhu, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Navigated+transcranial+magnetic+stimulation%5BTitle%5D)+AND+%22Neurophysiol+Clin%22%5BJournal%5D)">Navigated transcranial magnetic stimulation.</a> Neurophysiol Clin. 40 (1), 7-17 (2010).</li>
<li>Dell'Osso, B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Augmentative+repetitive+navigated+transcranial+magnetic+stimulation+%28rTMS%29+in+drug-resistant+bipolar+depression%5BTitle%5D)+AND+%22Bipolar+Disord%22%5BJournal%5D)">Augmentative repetitive navigated transcranial magnetic stimulation (rTMS) in drug-resistant bipolar depression.</a> Bipolar Disord. 11 (1), 76-81 (2009).</li>
<li>Herbsman, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((More+lateral+and+anterior+prefrontal+coil+location+is+associated+with+better+repetitive+transcranial+magnetic+stimulation+antidepressant+response%5BTitle%5D)+AND+%22Biol+Psychiatry%22%5BJournal%5D)">More lateral and anterior prefrontal coil location is associated with better repetitive transcranial magnetic stimulation antidepressant response.</a> Biol Psychiatry. 66 (5), 509-515 (2009).</li>
<li>Schuhmann, T., Schiller, N. O., Goebel, R., Sack, A. T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((The+temporal+characteristics+of+functional+activation+in+Broca%27s+area+during+overt+picture+naming%5BTitle%5D)+AND+%22Cortex%22%5BJournal%5D)">The temporal characteristics of functional activation in Broca's area during overt picture naming.</a> Cortex. 45 (9), 1111-1116 (2009).</li>
<li>Danner, N., Julkunen, P., Kononen, M., Saisanen, L., Nurkkala, J., Karhu, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Navigated+transcranial+magnetic+stimulation+and+computed+electric+field+strength+reduce+stimulator-dependent+differences+in+the+motor+threshold%5BTitle%5D)+AND+%22J+Neurosci+Methods%22%5BJournal%5D)">Navigated transcranial magnetic stimulation and computed electric field strength reduce stimulator-dependent differences in the motor threshold.</a> J Neurosci Methods. 174 (1), 116-122 (2008).</li>
<li>Bashir, S., Edwards, D., Pascual-Leone, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Neuronavigation+increases+the+physiologic+and+behavioral+effects+of+low-frequency+rTMS+of+primary+motor+cortex+in+healthy+subjects%5BTitle%5D)+AND+%22Brain+Topogr%22%5BJournal%5D)">Neuronavigation increases the physiologic and behavioral effects of low-frequency rTMS of primary motor cortex in healthy subjects.</a> Brain Topogr. 24 (1), 54-64 (2011).</li>
<li>Kim, W. J., Min, Y. S., Yang, E. J., Paik, N. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Neuronavigated+vs.+conventional+repetitive+transcranial+magnetic+stimulation+method+for+virtual+lesioning+on+the+Broca%27s+area%5BTitle%5D)+AND+%22Neuromodulation%22%5BJournal%5D)">Neuronavigated vs. conventional repetitive transcranial magnetic stimulation method for virtual lesioning on the Broca's area.</a> Neuromodulation. 17 (1), 16-21 (2014).</li>
<li>Lioumis, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((A+novel+approach+for+documenting+naming+errors+induced+by+navigated+transcranial+magnetic+stimulation%5BTitle%5D)+AND+%22J+Neurosci+Methods%22%5BJournal%5D)">A novel approach for documenting naming errors induced by navigated transcranial magnetic stimulation.</a> J Neurosci Methods. 204 (2), 349-354 (2012).</li>
<li>Hamilton, R. H., Chrysikou, E. G., Coslett, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Mechanisms+of+aphasia+recovery+after+stroke+and+the+role+of+noninvasive+brain+stimulation%5BTitle%5D)+AND+%22Brain+Lang%22%5BJournal%5D)">Mechanisms of aphasia recovery after stroke and the role of noninvasive brain stimulation.</a> Brain Lang. 118 (1-2), 40-50 (2011).</li>
<li>Pascual-Leone, A., Walsh, V., Rothwell, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Transcranial+magnetic+stimulation+in+cognitive+neuroscience--virtual+lesion%2C+chronometry%2C+and+functional+connectivity%5BTitle%5D)+AND+%22Curr+Opin+Neurobiol%22%5BJournal%5D)">Transcranial magnetic stimulation in cognitive neuroscience--virtual lesion, chronometry, and functional connectivity.</a> Curr Opin Neurobiol. 10 (2), 232-237 (2000).</li>
<li>Julkunen, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Comparison+of+navigated+and+non-navigated+transcranial+magnetic+stimulation+for+motor+cortex+mapping%2C+motor+threshold+and+motor+evoked+potentials%5BTitle%5D)+AND+%22Neuroimage%22%5BJournal%5D)">Comparison of navigated and non-navigated transcranial magnetic stimulation for motor cortex mapping, motor threshold and motor evoked potentials.</a> Neuroimage. 44 (3), 790-795 (2009).</li>
<li>Chrysikou, E. G., Hamilton, R. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Noninvasive+brain+stimulation+in+the+treatment+of+aphasia%3A+exploring+interhemispheric+relationships+and+their+implications+for+neurorehabilitation%5BTitle%5D)+AND+%22Restor+Neurol+Neurosci%22%5BJournal%5D)">Noninvasive brain stimulation in the treatment of aphasia: exploring interhemispheric relationships and their implications for neurorehabilitation.</a> Restor Neurol Neurosci. 29 (6), 375-394 (2011).</li>
</ol>

All authors declare no conflict of interest.

TMS is widely used both in clinical practice and basic research.10 Valuable therapeutic effects are offered by the physiologic influence of rTMS, including an inhibitory neuromodulatory effect on cortical excitability with low frequency rTMS for treatment of aphasia.11 Transient disruption of neural processing or virtual lesioning induced by rTMS can change behavioral performance.12 However, the desired effect of rTMS may be diluted or even not occur with the coil misplaced on the target....

Repetitive transcranial magnetic stimulation (rTMS) non-invasively activates neuronal circuits in the central and peripheral nervous systems.1 rTMS modulates brain excitability2 and has potential therapeutic effects in several psychiatric and neurological conditions, such as motor weakness, aphasia, neglect, and pain.3 The target sites for rTMS other than the motor cortex are conventionally identified using the International 10-20 EEG system or by measuring distances from certain external landmarks.
However, inter-individual differences in size, anatomy, and morphology of the brain cortex are not taken into account, making optimal target localization challenging.3 Another critical issue for rTMS applications is the discordance between placement of the magnetic coil and the cortical region of intended stimulation.
Optically tracked navigational neurosurgery has expanded it applications to encompass the cognitive neuroscience field including rTMS for guidance of the magnetic coil. The neuronavigational system assists in identifying the optimal target structures for rTMS.4,5 Such divergence in coil positioning on the target area frequently occurs with the conventional method adopting the 10-20 EEG system, and this is expected to be overcome by neuronavigation.
This study protocol demonstrates a method to induce virtual aphasia in healthy subjects by neuronavigational rTMS targeting Broca&#39;s area, using individual anatomical mapping. The degree of virtual aphasia in terms of change in reaction time to picture naming is measured and compared with those from the conventional stimulation method. The neuronavigation-guided method has higher accuracy for delivering magnetic pulses to the brain, and is thus expected to demonstrate greater clinical change than that of the conventional method. The goal of this study was to introduce a more precise and effective method of stimulation for patients with aphasia in clinical setting.

<table><tbody><tr><td>Medtronic MagPro X100</td><td>MagVenture</td><td>9016E0711</td><td></td></tr><tr><td>MCF-B65 Butterfly coil</td><td>MagVenture</td><td>9016E042</td><td></td></tr><tr><td>Brainsight TMS Navigation</td><td>Rogue Research</td><td>&lt;br/&gt; KITBSF1003&amp;nbsp;</td><td></td></tr></tbody></table>

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.

Kim et al.&#160;demonstrated a more superior effect of TMS with neuronavigational system guidance compared to the non-navigated conventional method by less dispersion of stimulus and more focal stimulation to the right M1 area,8 as shown in Figure 9. Further evidence to support incorporating the neuronavigational system with TMS is demonstrated by a randomized crossover experiment to induce virtual aphasia in healthy subjects by targeting Brodmann area...

Watch this Scientific Journal Video about Neuronavigation-guided Repetitive Transcranial Magnetic Stimulation for Aphasia at JoVE.com

Neuronavigation-guided Repetitive Transcranial Magnetic Stimulation for Aphasia

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 ...

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12.1K Views.  Inje University of Medicine, Haeundae Paik Hospital. 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.

Video: Neuronavigation-guided Repetitive Transcranial Magnetic Stimulation for Aphasia

Functional Magnetic Resonance Imaging (fMRI) with Auditory Stimulation in Songbirds

The neurobiology of birdsong, as a model for human speech, is a pronounced area of research in behavioral neuroscience. Whereas electrophysiology and molecular approaches allow the investigation of either different stimuli on few neurons, or one stimulus in large parts of the brain, blood oxygenation level dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) allows combining both advantages, i.e. compare the neural activation induced by different stimuli in the entire brain at once. fMRI in songbirds is challenging because of the small size of their brains and because their bones and especially their skull comprise numerous air cavities, inducing important susceptibility artifacts. Gradient-echo (GE) BOLD fMRI has been successfully applied to songbirds 1-5 (for a review, see 6). These studies focused on the primary and secondary auditory brain areas, which are regions free of susceptibility artifacts. However, because processes of interest may occur beyond these regions, whole brain BOLD fMRI is required using an MRI sequence less susceptible to these artifacts. This can be achieved by using spin-echo (SE) BOLD fMRI 7,8 . In this article, we describe how to use this technique in zebra finches (Taeniopygia guttata), which are small songbirds with a bodyweight of 15-25 g extensively studied in behavioral neurosciences of birdsong. The main topic of fMRI studies on songbirds is song perception and song learning. The auditory nature of the stimuli combined with the weak BOLD sensitivity of SE (compared to GE) based fMRI sequences makes the implementation of this technique very challenging.

Functional Magnetic Resonance Imaging fMRI with Auditory Stimulation in Songbirds

This article shows an optimized procedure for imaging of the neural substrates of auditory stimulation in the songbird brain using functional Magnetic Resonance Imaging (fMRI). It describes the preparation of the sound stimuli, the positioning of the subject and the acquisition and subsequent analysis of the fMRI data.

The neurobiology of birdsong, as a model for human speech, is a pronounced area of research in behavioral neuroscience. Whereas electrophysiology and ...

Best Current Practice for Obtaining High Quality EEG Data During Simultaneous fMRI

Simultaneous EEG-fMRI allows the excellent temporal resolution of EEG to be combined with the high spatial accuracy of fMRI. The data from these two modalities can be combined in a number of ways, but all rely on the acquisition of high quality EEG and fMRI data. EEG data acquired during simultaneous fMRI are affected by several artifacts, including the gradient artefact (due to the changing magnetic field gradients required for fMRI), the pulse artefact (linked to the cardiac cycle) and movement artifacts (resulting from movements in the strong magnetic field of the scanner, and muscle activity). Post-processing methods for successfully correcting the gradient and pulse artifacts require a number of criteria to be satisfied during data acquisition. Minimizing head motion during EEG-fMRI is also imperative for limiting the generation of artifacts.
Interactions between the radio frequency (RF) pulses required for MRI and the EEG hardware may occur and can cause heating. This is only a significant risk if safety guidelines are not satisfied. Hardware design and set-up, as well as careful selection of which MR sequences are run with the EEG hardware present must therefore be considered.
The above issues highlight the importance of the choice of the experimental protocol employed when performing a simultaneous EEG-fMRI experiment. Based on previous research we describe an optimal experimental set-up. This provides high quality EEG data during simultaneous fMRI when using commercial EEG and fMRI systems, with safety risks to the subject minimized. We demonstrate this set-up in an EEG-fMRI experiment using a simple visual stimulus. However, much more complex stimuli can be used. Here we show the EEG-fMRI set-up using a Brain Products GmbH (Gilching, Germany) MRplus, 32 channel EEG system in conjunction with a Philips Achieva (Best, Netherlands) 3T MR scanner, although many of the techniques are transferable to other systems.

Simultaneous electroencephalography (EEG) and functional Magnetic Resonance imaging (fMRI) is a powerful neuroimaging tool. However, the inside of an MRI scanner forms a difficult environment for EEG data recording and safety must be considered whenever operating EEG equipment inside a scanner. Here, we present an optimised EEG-fMRI data acquisition protocol.

Simultaneous  EEG-fMRI allows the excellent temporal resolution of EEG to be combined with the  high spatial accuracy of fMRI. The data  from these two ...

Simultaneous EEG Monitoring During Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a technique that delivers weak electric currents through the scalp. This constant electric current induces shifts in neuronal membrane excitability, resulting in secondary changes in cortical activity. Although tDCS has most of its neuromodulatory effects on the underlying cortex, tDCS effects can also be observed in distant neural networks. Therefore, concomitant EEG monitoring of the effects of tDCS can provide valuable information on the mechanisms of tDCS. In addition, EEG findings can be an important surrogate marker for the effects of tDCS and thus can be used to optimize its parameters. This combined EEG-tDCS system can also be used for preventive treatment of neurological conditions characterized by abnormal peaks of cortical excitability, such as seizures. Such a system would be the basis of a non-invasive closed-loop device. In this article, we present a novel device that is capable of utilizing tDCS and EEG simultaneously. For that, we describe in a step-by-step fashion the main procedures of the application of this device using schematic figures, tables and video demonstrations. Additionally, we provide a literature review on clinical uses of tDCS and its cortical effects measured by EEG techniques.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has shown initial therapeutic effects in several neurological conditions. The main mechanism underlying these therapeutic effects is the modulation of cortical excitability. Therefore, online monitoring of cortical excitability would help guide stimulation parameters and optimize its therapeutic effects. In the present article we review the use of a novel device that combines simultaneous tDCS and EEG monitoring in real time.

Transcranial  direct current stimulation (tDCS) is a technique that delivers weak electric  currents through the scalp. This constant electric current ...

Repetitive Transcranial Magnetic Stimulation to the Unilateral Hemisphere of Rat Brain

Previous rodent models of repetitive transcranial magnetic stimulation (rTMS) adopted whole-brain stimulation instead of unilateral hemispheric rTMS, which is unlike the protocols used for human subjects. We report a successful application of rTMS to the unilateral hemisphere of rat brain. The rTMS was delivered with a low-frequency (1 Hz), high-frequency (20 Hz), or sham stimulation protocol to one side of the brain by using a small 25-mm figure-8 coil. We placed the center of the coil 1 cm lateral to the vertex on the biauricular line and angulated the coil 45&#176; to the ground to minimize a potential direct effect of rTMS on the contralateral cortex. We also used an in-house water cooling system to enable repetitive magnetic stimulation for more than 20 min, even at a 20-Hz stimulation frequency. Increases in the transcriptions of immediate early genes (Arc, Junb, and Egr2) were greater after rTMS than after sham stimulation. After 5 consecutive days of 20-min 1-Hz rTMS, bdnf mRNA expression was significantly higher in stimulated cortex than in contralateral side. The model presented herein will elucidate the molecular mechanisms of rTMS by allowing analysis of the inter-hemispheric difference in its effect.

We applied repetitive transcranial magnetic stimulation (rTMS) to the unilateral hemisphere of rat brain, by placing a 25-mm figure-8 coil 1 cm lateral to the vertex on the biauricular line and angulating the coil by 45&#176;. An in-house water cooling system was used for rTMS for more than 20 min.

Previous rodent models of repetitive transcranial magnetic stimulation (rTMS) adopted whole-brain stimulation instead of unilateral hemispheric rTMS, ...

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 ...

Medicine

Individualized rTMS Treatment for Depression using an fMRI-Based Targeting Method

To achieve greater clinical efficacy, a revolution in treatment for major depressive disorder (MDD) is highly anticipated. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive and safe neuromodulation technique that immediately changes brain activity. Despite its wide application in the treatment for MDD, the treatment response remains different among individuals, which may be attributable to the inaccurate positioning of the stimulation target. Our study aims to examine whether the functional magnetic resonance imaging (fMRI)-assisted positioning improves the efficacy of rTMS in treating depression. We intend to identify and stimulate the subregion of dorsolateral prefrontal cortex (DLPFC) in MDD with strongest anti-correlation with the subgenual anterior cingulate cortex (sgACC), and to conduct a comparative investigation of this novel method and the traditional 5-cm rule. To achieve more precise stimulation, both methods were applied under the guidance of neuronavigation system. We expected that the TMS treatment with individualized positioning based on resting state functional connectivity may show better clinical efficacy than the 5-cm method.

The present protocol describes the application of repetitive transcranial magnetic stimulation (rTMS), where a subregion of the dorsolateral prefrontal cortex (DLPFC) with the strongest functional anticorrelation with the subgenual anterior cingulate cortex (sgACC) was located as the stimulation target under the assistance of a fMRI-based neuronavigation system.

To achieve greater clinical efficacy, a revolution in treatment for major depressive disorder (MDD) is highly anticipated. Repetitive transcranial ...

MRI-guided dmPFC-rTMS as a Treatment for Treatment-resistant Major Depressive Disorder

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial prefrontal cortex (dmPFC) in patients with major depressive disorder (MDD). Technicians used a neuronavigation system to process patient MRIs to generate a 3-dimensional head model. The head model was subsequently used to identify patient-specific stimulatory targets. The dmPFC was stimulated daily for 20 sessions. Stimulation intensity was titrated to address scalp pain associated with rTMS. Weekly assessments were conducted on the patients using the Hamilton Rating Scale for Depression (HamD17) and Beck Depression Index II (BDI-II). Treatment-resistant MDD patients achieved significant improvements on both HAMD and BDI-II. Of note, angled, double-cone coil rTMS at 120% resting motor threshold allows for optimal stimulation of deeper midline prefrontal regions, which results in a possible therapeutic application for MDD. One major limitation of the rTMS field is the heterogeneity of treatment parameters across studies, including duty cycle, number of pulses per session and intensity. Further work should be done to clarify the effect of stimulation parameters on outcome. Future dmPFC-rTMS work should include sham-controlled studies to confirm its clinical efficacy in MDD.

Here we outline the procedure for MRI-guided repetitive transcranial magnetic stimulation to the dorsomedial prefrontal cortex as an experimental treatment for major depressive disorder.

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial ...

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 ...

Neuroscience

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.

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 ...

Combined Intervention Training for Children with Spastic Cerebral Palsy 

Repeated Transcranial Magnetic Stimulation Combined with Action Observation Training in Children with Spastic Cerebral Palsy

This study presents the results of a randomized controlled trial utilizing a 2 x 2 factorial design, comparing the effects of repeated transcranial magnetic stimulation (rTMS) and action observation training (AOT) intervention methods on spasticity, balance function, and motor function in children with spastic cerebral palsy (SCP). The study aimed to investigate whether the combination of the two interventions produces greater improvement than either treatment alone or conventional treatment.
Subject children in this study, in accordance with the random number table, were randomly divided into four groups: conventional group, rTMS group, AOT group, and combined intervention group. All the children in the four groups received conventional rehabilitation treatment, on the basis of which they were given different therapeutic programs of rehabilitation measures. The conventional group had no other treatment while the rTMS group received rTMS, the AOT group received AOT and the combined intervention group was given a combined intervention of rTMS and AOT. They were trained five days per week for 12 weeks. Changes in scores of spasticity, balance function, walking ability, and gross motor function were assessed at the onset of the training program and upon completion of 12 weeks of treatment.
A total of 64 Children with SCP completed the study, and their results were analyzed. The total gross motor function efficiency of 87.50% in the experimental group was significantly higher than that of 25.00% in the conventional group, 62.50% in the rTMS group, and 68.75% in the AOT group. The preliminary results showed that combined intervention of rTMS and AOT could effectively improve the balance function and motor function of children, and the therapeutic effect of the combined intervention was better than that of conventional treatment, rTMS or AOT alone. Finally, clinical efficacy and optimal treatment parameters of the combined intervention were clarified to provide a clinical basis for therapists to conduct lower limb function rehabilitation for children with SCP.

Author Spotlight: Repetitive Transcranial Magnetic Stimulation Combined with Movement Observation in Cerebral Palsy

Children with spastic cerebral palsy (SCP) have limb spasticity, movement disorders, and abnormal posture due to injury to the cerebral cortex motor area, resulting in inability to stand and walk normally. Therefore, alleviating limb spasticity and enhancing gross motor function in children with SCP have become important therapeutic goals.

This study presents the results of a randomized controlled trial utilizing a 2 x 2 factorial design, comparing the effects of repeated transcranial ...