The effects of NMDA receptor blockade on TMS-evoked EEG potentials from prefrontal and parietal cortex

Abstract

Measuring the brain's response to transcranial magnetic stimulation (TMS) with electroencephalography (EEG) offers unique insights into the cortical circuits activated following stimulation, particularly in non-motor regions where less is known about TMS physiology. However, the mechanisms underlying TMS-evoked EEG potentials (TEPs) remain largely unknown. We assessed TEP sensitivity to changes in excitatory neurotransmission mediated by n-methyl-d-aspartate (NMDA) receptors following stimulation of non-motor regions. In fourteen male volunteers, resting EEG and TEPs from prefrontal (PFC) and parietal (PAR) cortex were measured before and after administration of either dextromethorphan (NMDA receptor antagonist) or placebo across two sessions in a doubleblinded pseudo-randomised crossover design. At baseline, there were amplitude differences between PFC and PAR TEPs across a wide time range (15-250 ms), however the signals were correlated after ~80 ms, suggesting early peaks reflect site-specific activity, whereas late peaks reflect activity patterns less dependent on the stimulated sites. Early TEP peaks were not reliably altered following dextromethorphan compared to placebo, although findings were less clear for later peaks, and low frequency resting oscillations were reduced in power. Our findings suggest that early TEP peaks (<80 ms) from PFC and PAR reflect stimulation site specific activity that is largely insensitive to changes in NMDA receptor-mediated neurotransmission.Transcranial magnetic stimulation (TMS) is a brain stimulation method capable of non-invasively activating cortical neurons across the scalp in humans via electromagnetic induction 1 . A single TMS pulse evokes a series of time-locked peaks and troughs in electroencephalographic (EEG) recordings of brain activity 2 , which are commonly known as TMS-evoked EEG potentials (TEPs). TEPs are reliable within and between sessions 3-5 , are sensitive to changes in TMS parameters such as intensity 4 and pulse shape 6 , and differ depending on the cortical site stimulated 4,7 . In addition, TEPs are sensitive to changes in cortical properties resulting from differing brain states, plasticity-inducing brain stimulation paradigms, and brain disorders 8 . As such, TMS-EEG is emerging as a powerful method for investigating cortical dynamics in health and disease.Despite the recent uptake of TMS-EEG within the brain stimulation field, it remains largely unclear what physiological properties underlie the size, shape and distribution of TEPs, thereby limiting their interpretability. Current hypotheses suggest that TEPs primarily reflect fluctuations in cortical excitability resulting from excitatory and inhibitory neurotransmission at the site of stimulation, as well as the propagation of activation through www.nature.com/scientificreports www.nature.com/scientificreports/ PFC (15-45 ms) 60 [18-133] 73 [40-103] 0.93 [0.81-0.99] 0.135 PFC (95-125 ms) 80 [24-129] 59 [20-110] 0.88 [0.68-0.99] 0.077 PFC (175-205 ms) 80 [37-123] 51 [21-122] 0.84 [0.69-0.99] 0....

Transcranial Evoked Potentials Can Be Reliably Recorded with Active Electrodes

“…A consensus on the best pre-processing pipeline has yet to be reached [ 1 ]; thus, we deemed it important to collect data about different pre-processing solutions. There are two main reasons why the two pipelines could have yielded different results, as in previous work [ 24 , 36 ]. The first pertains to the EEG artefact that is caused by scalp muscle activation, which is handled differently by SSP-SIR and ICA.…”

“…Subsequently, the signals were down-sampled to 1000 Hz, band-pass (1–100 Hz) and band-stop (48–52 Hz) filtered with a fourth order Butterworth filter. The epochs were restricted to (−1 to 1 s) in order to reduce possible edge artefacts, and a round of SOUND (source-estimate-utilizing noise-discarding algorithm) [ 23 ] was applied to further clean the signal (λ = 0.1, 20 iterations), as previously done with TMS-EEG data [ 24 ]. A second round of fastICA was then performed, plotting the full epoch length, to remove residual artefacts non time-locked with the TMS pulse (e.g., spontaneous eyeblinks and continuous muscle activity).…”

The impact of artifact removal approaches on TMS–EEG signal

“…Most of the studies on DLPFC stimulation agree on deflections such as the N40, P60, N100 and P185 (Bagattini et al, 2019;Chung et al, 2019;Conde et al, 2019;Gordon et al, 2018;Rogasch et al, 2014;Voineskos et al, 2019), but other peaks are often reported at ~30 ms, ~50 ms, or ~70 ms (Bagattini et al, 2019;Conde et al, 2019;Rogasch et al, 2014). For IPL, there is still little characterization of TEP components and the few studies that reported them have shown inconsistent results (Conde et al, 2019;Rogasch et al, 2020;Romero Lauro et al, 2014). According to our findings, the preprocessing phase could be a possible source of variability in TEPs' earlycomponent (<100 ms) definition.…”

Single-Pulse TMS to the Temporo-Occipital and Dorsolateral Prefrontal Cortex Evokes Lateralized Long Latency EEG Responses at the Stimulation Site

“…Therefore, we studied the spatiotemporal distribution of TEPs during the stimulation of the temporo-occipital cortex (TOC) and the DLPFC of both hemispheres. Although there is still uncertainty regarding late deflections (>80 ms), early TEPs (<80 ms) are more widely recognized to reflect activity of the stimulated cortex ( Herring et al, 2015 ; Du et al, 2017 ; Conde et al, 2019 ; Rogasch et al, 2020 ). We thus focused on late negative deflections corresponding to the N100 in motor cortex stimulation and expected to identify lateralized site-specific components over the stimulated brain region.…”