Saying goodbye to an unwelcome guest: towards robust methods for controlling multi‐sensory confounds in TMS‐EEG research

Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) is a multi-modal functional neuroimaging approach that has seen growing uptake across basic, cognitive, and clinical neuroscience as a method for safely interrogating cortical physiology in vivo. TMS uses a coil placed over the scalp to produce a brief, time-varying magnetic field capable of passing unimpeded through the skull to activate underlying neuronal populations (Barker et al., 1985). By combining TMS with EEG, the electrical neuronal response to stimulation can be captured across the cortex with millisecond temporal precision, providing insight into brain responsivity both at the stimulation site and across broader neural networks (Tremblay et al., 2019). As such, TMS-EEG has opened exciting new avenues for understanding healthy brain function and probing neuropathophysiological circuits across several psychiatric, neurological and neurodevelopmental disorders. However, in addition to transcranially stimulating cortical neuronal populations, TMS also exerts effects on brain function via indirect multi-sensory pathways. This includes activation of the auditory system through the ‘click’ sound generated when the TMS coil discharges, as well as via signal propagation through somatosensory pathways caused by stimulation of the scalp and vibration of the TMS coil. These sensory co-activations lead to peripherally evoked potentials (PEPs) on the EEG record, which, if not adequately accounted for, can obscure the TMS-evoked potentials (TEPs) arising from direct transcranial stimulation of the cortex. In this issue of The Journal of Physiology, Gordon et al. (2023) report results from a study aimed at better understanding TEPs and PEPs captured with TMS-EEG. To achieve their aim, the authors used an experimental approach incorporating both an optimised sham TMS protocol and pharmacological challenge. Healthy participants completed two experimental sessions during which TMS-EEG recordings were obtained both before and after administration of either a positive allosteric modulator of GABAA receptors (oral diazepam) or placebo. This pharmaco-TMS-EEG design enabled the authors to investigate changes in brain responses to a drug previously shown to alter cortical reactivity using TMS-EEG (Premoli et al., 2014). Gordon et al. (2023) implement a unique stimulation approach targeting motor cortex that interleaved active and sham stimulation within the same experimental block along with concomitant high-intensity electrical stimulation of the scalp. This sophisticated methodology enabled the authors to closely align the auditory and somatosensory inputs generated across these two conditions. There are, nevertheless, some potential caveats surrounding this approach. For instance, the use of electrical stimulation in close proximity to recording electrodes will unavoidably produce artifacts on the EEG trace – a limitation the authors themselves acknowledge. If not completely removed, this could distort or obscure TEPs, particularly at early time points. Also, given that the authors used high electrical stimulation intensities (average= 25.6 mA) to saturate the PEPs in both the active and sham TMS conditions, this raises interesting questions regarding intensities at which these might begin to induce meaningful physiological effects in the brain via injection of current through the scalp and skull. Although this is perhaps unlikely, given that the E-field induced in the brain would be diminished manyfold in comparison to TMS, it could be a potentially interesting avenue to explore in future research. A central finding by Gordon et al. (2023) was that modulation of GABAA receptor-mediated neurotransmission via diazepam was able to elicit demonstrable changes on the TMS-EEG record following both active and sham TMS. Specifically, diazepam attenuated late responses in both the active (>80 ms) and sham (>85 ms) conditions, while also enhancing the negativity of the P60 potential in the active TMS condition only. This indicates that cortical reactivity to both direct transcranial stimulation and sensory co-activation can be pharmacologically modulated. A further particularly interesting discovery relates to the N100 response. This prominent negative potential has been previously linked to cortical inhibitory processes, including by pharmaco-TMS-EEG studies using GABA receptor agonists (Premoli et al., 2014). However, the N100 is also sensitive to multi-sensory input (Biabani et al., 2019). The results of Gordon et al. (2023) indicate that although diazepam was able to attenuate the N100 amplitude in both the active and sham TMS conditions, after subtracting the sham from the active TMS response this effect disappeared. This raises the intriguing possibility that GABAA receptor-mediated modulation of the N100 via diazepam could in fact be driven by PEPs. The potential significance of this observation is substantial given that the N100 is frequently interpreted as reflecting cortical inhibition in motor cortex. Research is needed to assess the replicability of this result and would likely also benefit from the inclusion of a drug targeting GABAB receptors, given past links between the N100 and GABAB receptor-mediated inhibition (Tremblay et al., 2019). In summary, this timely study by Gordon et al. (2023) significantly contributes to ongoing endeavours to advance mechanistic understanding of neural responses captured using TMS-EEG. The findings corroborate growing evidence supporting the need for adequate control of PEPs on the TMS-EEG record, particularly when analysing later-occurring responses (i.e. >∼80 ms post-TMS). Thus, while continued empirical efforts will no doubt be required to further fine-tune best-practice