Combined Transcranial Magnetic Stimulation and Electroencephalography of the Dorsolateral Prefrontal Cortex

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.

This method can help answer key questions in the fields of neurology, clinical neurophysiology, and psychiatry by determining neurophysiological signals that may serve as predictors of response to therapeutic interventions. If properly performed, this technique can monitor, reliably and reproducibly, changes in cortical excitability due to these therapeutic interventions. Demonstrating the procedure will be Stacey Shim, a research analyst from our laboratory.

To start, first choose a cap that fits the participant's head well. Place the Cz electrode at vertex halfway between the line connecting the nasian and inian. Ensure that all electrodes are tightly touching the scalp and are functioning.

Next, adjust the blunt tip of a syringe and fill it with electroconductive gel. Place the tip inside the electrode hole, and then lightly press the plunger until there is some paste on the skin. Then, scrub the scalp with the blunt tip and ensure that paste does not spill out over the top to avoid bridging.

Prepare the ground and reference electrodes first. Check that the impedance is under five kiloohms for all electrodes. Electrode preparation determines the quality of the recorded brain signal and minimizes the need of signal processing methods that may remove both noise and brain signal crucial for its study.

Now place two disposable EMG disk electrodes with a diameter of about 30 millimeters over the right abductor pollicis brevis muscle, or APB, for a belly-tendon montage. Also place the ground electrode according to the manufacturer's guidelines. Connect the electrodes to the EMG amplifier.

Begin by loading a T1-weighted MRI into the navigation system and choosing the cardinal points for registration. Use either MNI or Talairach coordinates of the dorsolateral prefrontal cortex. Then place the head tracker in such a way so that it will not move during the stimulation session, and allow the TMS coil to move freely.

Next have the participant insert earplugs, then align the participant's head to the 3D MRI model. To do this, touch the participant's head with the digitizing pen at the cardinal points selected in the MRI. Now validate the registration by placing the digitizing pen on the participant's head and checking the representation on the computer.

If needed, calibrate the TMS coil by attaching the trackers to the coil. Then place a polyurethane sponge under the coil to minimize the coil vibration over the electrodes during the TMS pulses. Place the coil on the calibration block so all the trackers are visible from the camera.

Then press the calibration button on the computer screen and keep the coil in the calibration position for five seconds. At this point, instruct the participant to rest and remain comfortable with a relaxed back, hands, and legs. Then to find the hotspot, begin by targeting the motor knob as the initial landmark of cortical representation of APB and primary motor cortex, and move the coil until there is corresponding muscle movement.

Use TMS intensities evoking motor-evoked thresholds or MEPs of around 500 microvolts over APB. Optimize the coil orientation by changing its angle and tilt to evoke the largest response over the hotspot. Save this coil positioning in the neuronavigator software and reduce the output intensity in steps of 2-3%Then give 10 pulses, and if more than five out of 10 MEP responses over 50 microvolts are obtained, continue reducing the intensity.

When less than five out of 10 responses are evoked, start increasing the intensity by steps of 1-2%Motor threshold is represented as the intensity that produces MEPs larger than 50 microvolts five out of 10 times. The interstimulus interval, ISI, for motor threshold should be longer than one second, usually three to five seconds. Next, adjust intensity starting at 120%of motor threshold to produce MEPs over primary motor cortex from 500 to 1500 microvolts.

Record 10 pulses with this output, increasing or decrease the intensity in steps of 1-2%until reaching an average of one microvolt. The adjustment of the coil intensity is crucial for targeting the neuronal population under investigation, but also for the quality of the signals. At this point, position the coil over dorsolateral prefrontal cortex and stimulate a few times.

If significant artifacts are generated, fine tune the coil placement by moving it slightly away from this location. Now digitize the EEG electrodes so that their position is registered to the brain anatomy. Then replace the earplugs with pneumatic audio earbuds to play white noise audio masking, if desired.

And add headphones over them for hearing protection. At this point, mount the coil on the coil holder and make sure that the coil does not move or press the electrodes under it. Finally, run the experiment including single-pulse TMS as well paired-pulse TMS for short intracortical inhibition, intracortical facilitation, and long intracortical inhibition, in a random order for each participant.

This figure shows the grand averages of TMS-evoked EEG responses from the dorsolateral prefrontal cortex region of interest electrodes after stimulation. This includes single-pulse TMS, short intracortical inhibition, intracortical facilitation, and long intracortical inhibition. Here we see N100 evoked potential values plotted topographically across all electrodes for each stimulation condition.

While attempting this procedure, it's important to prepare the electrodes accurately, to choose the correct stimulation target, and to adjust the stimulation intensity and coil orientation properly. After its development, this technique paved the way for researchers in the field of neuroscience, neurology, clinical neurophysiology, and psychiatry, to explore the corticocortical excitability and connectivity in various brain states, for both healthy volunteers and patients.