Neuronavigation-guided Repetitive Transcranial Magnetic Stimulation for Aphasia

Ethics statement: This study was approved by the institutional review board of a blinded hospital.

1. Preparing Materials (Table 1)

1. 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 µsec.
2. 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)
3. 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.
4. Record reaction time for each picture using a voice recording system, described in more detail in step 4.
5. Analyze latency and duration of the picture naming response by a voice analysis system, described in more detail in step 4.

2. Checking the Study Design

1. Use rTMS to Induce Virtual Aphasia.
   1. Ask the subject to perform the picture naming task, described in more detail in step 4. Picture naming task.
   2. 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.
2. Measure reaction time and error rate for picture naming and compare the results under both conditions, as described in more detail in step 4.

3. Preparation of the TMS Protocol

1. Determine RMT
   1. Place the active electrode on the left first dorsal interosseous (FDI) muscle.
   2. Deliver 10 consecutive stimulations to the right M1 area at a 4-6 sec interstimulus interval, checking the contraction of the left FDI muscle.
   3. Determine subject'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.
2. TMS Mapping
   1. 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.
      1. Reconstruct the skin structure
         1. Obtain the file of the subject's brain MR image in standard Digital Imaging and Communications in Medicine (DICOM). format. Convert the MR image by selecting "convert study". 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.
         2. Transfer the DICOM file to the computer in which the neuronavigation program is installed. Implement the navigation program. The default icon is "Anatomical." For a new patient record, select one of the DICOM image files.
         3. Click "Atlas spaces". This step is to set the reference point to reconstruct each image. Press "new" in the dropbox and set the reference anatomical structure by clicking" manual (AC-PC box)".
         4. Find the patient'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 "set AC".
         5. Find the patient'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 "set PC".
         6. Click "Reconstructions" to make the skin structure. Press "new" in the dropbox to select "Skin". Set the range for reconstruction on the MR images. Be sure to include the whole skull with the nasal tip and both ears.
         7. Click "compute skin" in the new structure. Wait until the process is done. After completion of skin construction, skin morphology should be displayed.
      2. Select "Full brain curvilinear" in the "Reconstruction" 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 "compute curvilinear". Full brain curvilinear should be displayed after construction is completed.
   2. 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).
      1. Click the "Landmark" 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 "new" and store it as "Landmark 1"
      2. Mark the nasal tip after registering nasion as landmark 1. Register the nasal tip by clicking " new" and store it as "Landmark 2"
      3. 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 "new" landmarks. For this protocol, the right tragus is registered as "Landmark 3" and the left is registered as "Landmark 4".
   3. Put the head strap with the subjective tracker on the participant'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.
      1. Calibrating the coil with the seating system.
         1. Calibrate the coil tracker before every nTMS stimulation. At the main computer menu, select "Window". Click "TMS coil calibration" in the dropbox. Click "new calibrate". At the second session, select the coil name used the first time and click "Re-calibrate".
         2. 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 "Begin calibration countdown", and a 5 sec of countdown will start. Hold the coil still during the countdown.

4. Picture Naming Task

1. Set the picture naming program to present each stimulus for 3,000 msec before automatically moving onto the next picture.
2. Ask the participant to name the presented picture as accurately and quickly as possible.
3. 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.
   1. 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).

5. TMS Mapping Protocol

1. Deliver1 Hz stimulation at an intensity of 90% of RMT for 10 min, with a total of 600 TMS pulses.
2. Hold the figure-eight coil tangentially to the skull with the coil perpendicularly oriented to the target.
3. TMS Mapping (Figure 7)
   1. Identify the anatomical inferior frontal gyrus (IFG) based on the surface of the normalized brain, for nTMS.
      1. Register the IFG as the nTMS target.
         1. Click "Target" and press "Configure targets". 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 "Trajectory".
      2. Register landmarks with the subjects scalp.
         1. Click "Sessions" for mapping. Create a new session by selecting "Online session" in the new dropbox. A "Session 1" window is created, within which the default icon is "Targets". Select the target name saved in step 3.2.2.2. (Select "Trajectory 1"). Click the "Add" button, and move to the next step.
         2. Click "Registration". 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.
         3. Make sure the camera identifies both the pointer and the subject tracker, displayed in green color. Point to the subject's nasion with the pointer. Click "Sample % Go to Next Landmark". Point to the subject's nasal tip and sample it. Repeat until all four landmarks are matched.
   2. Place the coil on F3 of the 10-20 international EEG system⁷ for cTMS.
4. 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'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's eye (Figure 8). Referring to the screen, the operator adjusts the coil on the target as it is moved away.
   1. Perform nTMS over the registered target
      1. Click "Perform" on the screen after registering the subject'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 "Driver" dropbox. Make sure the camera identifies both the subject tracker and coil tracker.
      2. 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's eye as much as possible.
5. 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.

6. Topograhic Data Acquisition

1. Record coil location per stimulation by manually pressing the " record" button on the remote control.
2. Upon recording each stimulation, acquires Taliarach coordinates in the x, y, z for the designated target and actual stimulated area.
3. Depict the coordinates on a single normalized brain using the freeware image processing program (MRIcro, http://www.mccauslandcenter.sc.edu/mricro/mricro/index.html).
4. 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, http://www.talairach.org/client.html).