Combined Transcranial Magnetic Stimulation and Electroencephalography of the Dorsolateral Prefrontal Cortex

Transcranial magnetic stimulation (TMS) is a neurophysiological tool that allows for the non-invasive assessment of cortical neuronal activity through the use of rapid, time-varying magnetic field pulses¹. These magnetic field pulses induce a weak current in the superficial cortex beneath the coil which results in membrane depolarization. The ensuing cortical activation or modulation is directly related to the characteristics of the coil, its angle and orientation to the skull². The waveform of the pulse discharged from the coil and the underlying state of the neurons also influence the resultant cortical activation³.

TMS enables the assessment of cortical functions by evoking behavioral or motor responses or through the interruption of task-related processing. The excitability of cortico-spinal processes can be evaluated through recording electromyographic (EMG) responses elicited from single TMS pulses over the motor cortex, whereas intracortical excitatory (intracortical facilitation; ICF) and inhibitory mechanisms (short and long intracortical inhibition; SICI and LICI) can be probed with paired-pulse TMS. Repetitive TMS can disturb various cognitive processes, but is primarily used as a therapeutic tool for a variety of neuropsychiatric disorders. Furthermore, the combination of TMS with simultaneous electroencephalography (TMS-EEG) can be used to assess cortico-cortical excitability and connectivity⁴. Finally, if the administration of TMS is delivered with neuronavigation (nTMS), it will allow for precise test-retest paradigms since the exact site of the stimulation can be recorded. Most of the cortical mantle can be targeted and stimulated (including those areas that do not produce measurable physical or behavioral responses) thus the cortex can be functionally mapped.

The EEG signal evoked from single or paired pulse TMS can facilitate the assessment of cortico-cortical connectivity⁵ and the current state of the brain. The TMS-induced electric current results in action potentials that can activate synapses. The distribution of the postsynaptic currents can be recorded through EEG⁶. The EEG signal can be used to quantify and locate synaptic current distributions through dipole modelling⁷ or minimum-norm estimation⁸, when multichannel EEG is employed, and with the conductivity structure of the head accounted for. Combined TMS-EEG can be employed to study cortical inhibitory processes⁹, oscillations¹⁰, cortico-cortical¹¹ and interhemispheric interactions¹², and cortical plasticity¹³. Most importantly, TMS-EEG can probe excitability changes during cognitive or motor tasks with good test-retest reliability^14,15. Importantly, TMS-EEG has the potential to determine neurophysiological signals that may serve as the predictors of response to therapeutic interventions (rTMS or pharmacological effects) in test-retest designs^16,17.

The principles of neuronavigation for TMS is based on the principles of frameless stereotaxy. The systems use an optical tracking system¹⁸ that employs a light-emitting camera that communicates with light-reflecting optical elements attached to both the head (via a reference tracker) and the TMS coil. Neuronavigation allows for coil localization on the 3-D MRI model with the aid of a digitizing reference tool or pen. The use of neuronavigation facilitates the capture of the coil orientation, location and alignment to the subject's head as well as the digitization of the EEG electrode positions. These features are essential for test-retest design experiments and for accurate stimulation of a specified location within dorsolateral prefrontal cortex.

In order to utilize a TMS-EEG protocol in a test-retest experiment, there needs to be accurate targeting and consistent stimulation of the cortical region to obtain reliable signals. TMS-EEG recording can be vulnerable to different artifacts. The TMS induced artifact on the EEG electrodes can be filtered with amplifiers that can recover after a delay^19,20 or with amplifiers that cannot be saturated²¹. However, other types of artifact generated by eye movements or blinks, cranial muscle activation in proximity to the EEG electrodes, random electrode movement and their polarization, and by the coil click or somatic sensation must be taken into consideration. Careful subject preparation that ensures electrode impedances below 5 kΩ, immobilization of the coil over the electrodes and a foam between coil and electrodes to reduce vibration (or a spacer to eliminate low frequency artifacts²²), earplugs and even auditory masking should be used to minimize these artifacts²³. The protocol presented here introduces a standard process for assessing neurophysiological functioning when the stimulation is applied over the dorsolateral prefrontal (DLPFC). The focus is on common paired-pulse paradigms that have been validated in the studies of M1^9,15,16.