Paired-pulse TMS and scalp EEG reveal systematic relationship between inhibitory GABA_a signaling in M1 and fronto-central cortical activity during action stopping

Abstract

By stopping actions even after their initiation, humans can flexibly adapt ongoing behavior to changing circumstances. The neural processes underlying the inhibition of movement during action-stopping are still controversial. In the 1990s, a fronto-central event-related potential (ERP) was discovered in the human EEG response to stop-signals in the classic stop-signal task, alongside a proposal that this "stop-signal P3" reflects an inhibitory process. Indeed, both amplitude and onset of the stop-signal P3 relate to overt behavior and movement-related EEG activity in ways predicted by the dominant models of action-stopping. However, neither EEG nor behavior allow direct inferences about the presence or absence of neurophysiological inhibition of the motor cortex, making it impossible to definitively relate the stop-signal P3 to inhibition. Here, we therefore present a multi-method investigation of the relationship between the stop-signal P3 and GABAergic signaling in primary motor cortex, as indexed by paired-pulse transcranial magnetic stimulation. In detail, we measured short-interval intracortical inhibition (SICI, a marker of inhibitory GABAa activity in M1) in a group of 41 human participants who also performed the stop-signal task while undergoing EEG recordings. In line with the P3-inhibition hypothesis, we found that subjects with stronger inhibitory GABA activity in M1 also showed both faster onsets and larger amplitudes of the stop-signal P3. This provides direct evidence linking the properties of this ERP to a true physiological index of motor system inhibition. We discuss these findings in the context of recent theoretical developments and empirical findings regarding the neural implementation of motor inhibition.

Multiple Brain Sources Are Differentially Engaged in the Inhibition of Distinct Action Types

“…The component that best represented the inhibitory activity in the discrete experiment exhibited the by-now classic correlates of action inhibition, namely, increasing Delta/Theta power and a large evoked P3 wave. The relevance of this IC-D for inhibition was confirmed by the significant SSRT D /P3 latency correlation across participants, in line with previous stop-signal task studies (Huster et al, 2020;Hynd et al, 2021;Wessel & Aron, 2015). Crucially, its inability to disentangle ERPs pertaining to the rhythmic ABORT R and CONTINUE R conditions revealed that the IC-D is functionally irrelevant in aborting ongoing rhythmic movements.…”

“…The absence of a significant P3 when evaluating the IC-D activity in the rhythmic experiment or, inversely, the IC-R activity in the discrete one suggests that the P3 signature is specific to the engaged inhibition brain component. This pattern of findings indicates that P3 is a clear-cut neural marker of action inhibition in the context of stop-signal reactions (Fine et al, 2020;Hynd et al, 2021;Tatz et al, 2021;Wessel & Aron, 2015). In addition, an N2 wave was exclusively evoked by the IC-R in the rhythmic ABORT R but not in any other condition.…”

“…This inhibitory network acts downstream on the brain "action network" that generates action through cortical and subcortical activations (Apšvalka et al, 2020;Aron et al, 2016;Bari & Robbins, 2013;Stinear et al, 2009). In the stop-signal paradigm, the standard task used in the domain, this inhibitory network underlies the successful cancelation of discrete action, as revealed by EEG evoked N2 and P3 potentials and increasing power of Delta (1-3 Hz) and Theta (4-7 Hz) oscillations (e.g., Huster et al, 2013;Hynd et al, 2021). These frontocentral EEG patterns proved to correlate with action cancelation across various inhibition situations (Dutra et al, 2018;Waller et al, 2019;Wessel & Aron, 2014).…”

Adjustments to Proactive Motor Inhibition without Effector-Specific Foreknowledge Are Reflected in a Bilateral Upregulation of Sensorimotor β-Burst Rates

“…All procedures were approved by the University of Iowa's institutional review board (IRB #201511709). The same data were used to investigate a hypothesis about the fronto-central P3 event-related potential in the context of reactive inhibitory control (Hynd, Soh, Rangel, & Wessel, 2021).…”

Partial response electromyography as a marker of action stopping

“…by blocking the direct pathway output by increased inhibition via the sub-thalamic nucleus, or by direct inhibitory influences on M1; e.g. Hynd et al, 2021). Complementary simultaneous data from brain imaging and neural stimulation studies are necessary to understand the neural mechanisms that cause the halt in muscle activity.…”