TMS-EEG Methodological advancement

Advancing TMS-EEG Methodologies for Probing Prefrontal Cortical Excitability and Inhibition

In my research on neuromodulation for psychiatric disorders, particularly treatment-resistant depression (TRD), I have contributed to several studies using transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) to characterize cortical responses in the dorsolateral prefrontal cortex (DLPFC). This work focuses on disentangling true cortical reactivity from sensory artifacts, optimizing stimulation parameters, and exploring how ongoing brain oscillations influence TMS outcomes. These efforts align with my goal of developing reliable biomarkers and personalized interventions to enhance therapeutic efficacy.

A foundational contribution was developing and validating a standardized protocol for neuronavigated TMS-EEG (nTMS-EEG) targeting the DLPFC (Lioumis et al., 2018). This method enables precise, reproducible assessment of cortical excitability and cortico-cortical connectivity, incorporating single-pulse TMS for excitability and paired-pulse paradigms for short intracortical inhibition (SICI), long intracortical inhibition (LICI), and intracortical facilitation (ICF). Applied in healthy volunteers and patients with depression, it facilitates test-retest paradigms to monitor changes from treatments like repetitive TMS (rTMS), magnetic seizure therapy (MST), and electroconvulsive therapy (ECT), while addressing artifacts through masking and careful coil positioning.

Centered image — TMS-EEG measures of cortical excitability. (A) Grand average of TMS-evoked EEG responses from DLPFC ROI electrodes after DLPFC stimulation. (B) N100 values plotted topographically across all electrodes for each session.

Building on this methodology, one key study examined the dose-response effects of intermittent theta-burst stimulation (iTBS) on DLPFC activity (Desforges et al., 2022). We compared 600, 1200, and 1800 pulses using TMS-EEG in healthy participants, finding no significant differences in modulation of TMS-evoked potentials (TEPs) or oscillatory activity across doses. However, all iTBS conditions altered TEP components (e.g., P30, N45, P60, P200) and reduced theta-band power, suggesting a common mechanism involving excitation-inhibition balance. This implies that higher doses may not necessarily amplify prefrontal potentiation, informing clinical protocols for TRD. To promote reproducibility, I have made the Matlab code for preprocessing and analyzing significant current density (SCD) and current scattering (SCS) metrics from this study openly available in my GitHub repository: github.com/ItayHadas/DLPFC_SCD_SCS_analysis. The repository includes automated TMS-EEG pipelines (based on the AARATEP Pipeline Cline et al., 2021), Brainstorm-based source localization and time-series analysis scripts, and statistical analysis tools like repeated-measures ANOVA for evaluating iTBS effects between diffrent doses and study phases.

We also addressed sensory confounds in TMS-EEG signals. In Poorganji et al. (Poorganji et al., 2021), we differentiated cortical from auditory responses using single-pulse (SP) and paired-pulse (PP; LICI) protocols over DLPFC. Active TMS elicited larger TEPs (e.g., N100-P200 amplitude) and broader oscillatory inhibition compared to sham, confirming that true cortical effects dominate when artifacts are controlled. Similarly, in Poorganji et al. (Poorganji et al., 2023), we isolated somatosensory and auditory artifacts during suprathreshold stimulation, showing that masking (e.g., foam spacers and noise) attenuates non-cortical contributions while preserving significant cortical excitability and inhibition metrics like cortical evoked activity (CEA) and global mean field amplitude (GMFA).

Further, we investigated how pre-stimulus brain states affect TMS responses. In Poorganji et al. (Poorganji et al., 2023), analyzing 64 datasets from healthy participants, we found that pre-TMS oscillatory power (but not phase) in theta and beta bands predicted DLPFC excitability. High-power states amplified post-TMS activity, and we introduced a “corrected_effect” metric to isolate TMS-specific contributions from spontaneous oscillations. This highlights the potential for power-thresholded TMS to reduce response variability.

These studies, where I contributed to experimental design, data analysis (e.g., EEG source localization, connectivity), protocol development, and biomarker validation, underscore TMS-EEG’s value for mechanistic insights into prefrontal circuits associated with mental conditions. Looking ahead, I aim to extend this to clinical populations, integrating multimodal data (e.g., fMRI, EEG) for predictive biomarkers in TRD trials, ultimately enabling state-informed, personalized neuromodulation.

References

2023

Isolating sensory artifacts in the suprathreshold TMS-EEG signal over DLPFC

Mohsen Poorganji, Reza Zomorrodi, Colin Hawco, and 8 more authors

Scientific Reports, Apr 2023

Abs DOI

Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) is an effective way to evaluate neurophysiological processes at the level of the cortex. To further characterize the TMS-evoked potential (TEP) generated with TMS-EEG, beyond the motor cortex, we aimed to distinguish between cortical reactivity to TMS versus non-specific somatosensory and auditory co-activations using both single-pulse and paired-pulse protocols at suprathreshold stimulation intensities over the left dorsolateral prefrontal cortex (DLPFC). Fifteen right-handed healthy participants received six blocks of stimulation including single and paired TMS delivered as active-masked (i.e., TMS-EEG with auditory masking and foam spacing), active-unmasked (TMS-EEG without auditory masking and foam spacing) and sham (sham TMS coil). We evaluated cortical excitability following single-pulse TMS, and cortical inhibition following a paired-pulse paradigm (long-interval cortical inhibition (LICI)). Repeated measure ANOVAs revealed significant differences in mean cortical evoked activity (CEA) of active-masked, active-unmasked, and sham conditions for both the single-pulse (F(1.76, 24.63) = 21.88, p \textless 0.001, η2 = 0.61) and LICI (F(1.68, 23.49) = 10.09, p \textless 0.001, η2 = 0.42) protocols. Furthermore, global mean field amplitude (GMFA) differed significantly across the three conditions for both single-pulse (F(1.85, 25.89) = 24.68, p \textless 0.001, η2 = 0.64) and LICI (F(1.8, 25.16) = 14.29, p \textless 0.001, η2 = 0.5). Finally, only active LICI protocols but not sham stimulation ([active-masked (0.78 ± 0.16, P \textless 0.0001)], [active-unmasked (0.83 ± 0.25, P \textless 0.01)]) resulted in significant signal inhibition. While previous findings of a significant somatosensory and auditory contribution to the evoked EEG signal are replicated by our study, an artifact attenuated cortical reactivity can reliably be measured in the TMS-EEG signal with suprathreshold stimulation of DLPFC. Artifact attenuation can be accomplished using standard procedures, and even when masked, the level of cortical reactivity is still far above what is produced by sham stimulation. Our study illustrates that TMS-EEG of DLPFC remains a valid investigational tool.
Pre-Stimulus Power but Not Phase Predicts Prefrontal Cortical Excitability in TMS-EEG

Mohsen Poorganji, Reza Zomorrodi, Christoph Zrenner, and 10 more authors

Biosensors, Feb 2023

Number: 2 Publisher: Multidisciplinary Digital Publishing Institute

Abs DOI

The cortical response to transcranial magnetic stimulation (TMS) has notable inter-trial variability. One source of this variability can be the influence of the phase and power of pre-stimulus neuronal oscillations on single-trial TMS responses. Here, we investigate the effect of brain oscillatory activity on TMS response in 49 distinct healthy participants (64 datasets) who had received single-pulse TMS over the left dorsolateral prefrontal cortex. Across all frequency bands of theta (4–7 Hz), alpha (8–13 Hz), and beta (14–30 Hz), there was no significant effect of pre-TMS phase on single-trial cortical evoked activity. After high-powered oscillations, whether followed by a TMS pulse or not, the subsequent activity was larger than after low-powered oscillations. We further defined a measure, corrected_effect, to enable us to investigate brain responses to the TMS pulse disentangled from the power of ongoing (spontaneous) oscillations. The corrected_effect was significantly different from zero (meaningful added effect of TMS) only in theta and beta bands. Our results suggest that brain state prior to stimulation might play some role in shaping the subsequent TMS-EEG response. Specifically, our findings indicate that the power of ongoing oscillatory activity, but not phase, can influence brain responses to TMS. Aligning the TMS pulse with specific power thresholds of an EEG signal might therefore reduce variability in neurophysiological measurements and also has the potential to facilitate more robust therapeutic effects of stimulation.

2022

Dose-response of intermittent theta burst stimulation of the prefrontal cortex: A TMS-EEG study

Manon Desforges, Itay Hadas, Brian Mihov, and 8 more authors

Clinical Neurophysiology, Jan 2022

Abs DOI

Objective Using concurrent transcranial magnetic stimulation (TMS) and electroencephalography (TMS-EEG), this study aims to compare the effect of three intermittent theta-burst stimulation (iTBS) doses on cortical activity in the left dorsolateral prefrontal (DLPFC) cortex. Methods Fourteen neurotypical participants took part in the following three experimental conditions: 600, 1200 and 1800 pulses. TMS-EEG recordings were conducted on the left DLPFC pre/post iTBS, including single-pulse TMS and short- and long-interval intracortical inhibition (SICI, LICI). TMS-evoked potentials (TEP) and event-related spectral perturbation (ERSP) were quantified. Linear mixed models were used to assess the effect of iTBS on brain activity. Results The effects of iTBS on DLPFC activity did not significantly differ between the three doses. Specifically, regardless of dose, iTBS modulated the amplitude of most TEP components (P30, N45, P60, P200), reduced SICI and LICI ratios of P30 and P200, and decreased ERSP power of theta oscillations. Conclusions In neurotypical individuals, doubling or tripling the number of iTBS pulses does not result in stronger potentiation of prefrontal activity. However, all iTBS conditions induced significant modulations of DLPFC activity. Significance Replicating the study in clinical populations could help define optimal parameters for clinical applications.

2021

Differentiating transcranial magnetic stimulation cortical and auditory responses via single pulse and paired pulse protocols: A TMS-EEG study

Mohsen Poorganji, Reza Zomorrodi, Colin Hawco, and 8 more authors

Clinical Neurophysiology, Aug 2021

Number: 8 0 citations (Crossref) [2021-06-20]

Abs DOI

Objective We measured the neurophysiological responses of both active and sham transcranial magnetic stimulation (TMS) for both single pulse (SP) and paired pulse (PP; long interval cortical inhibition (LICI)) paradigms using TMS-EEG (electroencephalography). Methods Nineteen healthy subjects received active and sham (coil 90° tilted and touching the scalp) SP and PP TMS over the left dorsolateral prefrontal cortex (DLPFC). We measured excitability through SP TMS and inhibition (i.e., cortical inhibition (CI)) through PP TMS. Results Cortical excitability indexed by area under the curve (AUC(25-275ms)) was significantly higher in the active compared to sham stimulation (F(1,18) = 43.737, p \textless 0.001, η2 = 0.708). Moreover, the amplitude of N100-P200 complex was significantly larger (F(1,18) = 9.118, p \textless 0.01, η2 = 0.336) with active stimulation (10.38 ± 9.576 µV) compared to sham (4.295 ± 2.323 µV). Significant interaction effects were also observed between active and sham stimulation for both the SP and PP (i.e., LICI) cortical responses. Finally, only active stimulation (CI = 0.64 ± 0.23, p \textless 0.001) resulted in significant cortical inhibition. Conclusion The significant differences between active and sham stimulation in both excitatory and inhibitory neurophysiological responses showed that active stimulation elicits responses from the cortex that are different from the non-specific effects of sham stimulation. Significance Our study reaffirms that TMS-EEG represents an effective tool to evaluate cortical neurophysiology with high fidelity.

2018

Combined Transcranial Magnetic Stimulation and Electroencephalography of the Dorsolateral Prefrontal Cortex

Pantelis Lioumis, Reza Zomorrodi, Itay Hadas, and 2 more authors

JoVE (Journal of Visualized Experiments), Aug 2018

Number: 138

Abs DOI

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).