Biophysical modeling of frontocentral ERP generation links circuit-level mechanisms of action-stopping to a behavioral race model.

Human frontocentral event-related potentials (FC-ERPs) are ubiquitous neural correlates of cognition and control, but their generating multiscale mechanisms remain mostly unknown. We used the Human Neocortical Neurosolver(HNN)'s biophysical model of a canonical neocortical circuit under exogenous thalamic and cortical drive to simulate the cell and circuit mechanisms underpinning the P2, N2, and P3 features of the FC-ERP observed after Stop-Signals in the Stop-Signal task (SST; N = 234 humans, 137 female). We demonstrate that a sequence of simulated external thalamocortical and cortico-cortical drives can produce the FC-ERP, similar to what has been shown for primary sensory cortices. We used this model of the FC-ERP to examine likely circuit-mechanisms underlying FC-ERP features that distinguish between successful and failed action-stopping. We also tested their adherence to the predictions of the horse-race model of the SST, with specific hypotheses motivated by theoretical links between the P3 and Stop process. These simulations revealed that a difference in P3 onset between successful and failed Stops is most likely due to a later arrival of thalamocortical drive in failed Stops, rather than, for example, a difference in effective strength of the input. In contrast, the same model predicted that early thalamocortical drives underpinning the P2 and N2 differed in both strength and timing across stopping accuracy conditions. Overall, this model generates novel testable predictions of the thalamocortical dynamics underlying FC-ERP generation during action-stopping. Moreover, it provides a detailed cellular and circuit-level interpretation that supports links between these macroscale signatures and predictions of the behavioral race model.Significance statement The frontocentral event-related potential (FC-ERP) is an easily-measurable neural correlate of cognition and control. However, the cortical dynamics that produce this signature in humans are complex, limiting the ability of researchers to make predictions about its underlying mechanisms. In this study, we used the biophysical model included in the open-source Human Neocortical Neurosolver software to simulate and evaluate the likely cellular and circuit mechanisms that underlie the FC-ERP in the Stop-Signal task. We modeled mechanisms of the FC-ERP during successful and unsuccessful stopping, generating testable predictions regarding Stop-associated computations in human frontal cortex. Moreover, the resulting model parameters provide a starting point for simulating mechanisms of the FC-ERP and other frontal scalp EEG signatures in other task conditions and contexts.

Biophysical modeling of frontocentral ERP generation links circuit-level mechanisms of action-stopping to a behavioral race model.

Human frontocentral event-related potentials (FC-ERPs) are ubiquitous neural correlates of cognition and control, but their generating multiscale mechanisms remain mostly unknown. We used the Human Neocortical Neurosolver(HNN)'s biophysical model of a canonical neocortical circuit under exogenous thalamic and cortical drive to simulate the cell and circuit mechanisms underpinning the P2, N2, and P3 features of the FC-ERP observed after Stop-Signals in the Stop-Signal task (SST). We demonstrate that a sequence of simulated external thalamocortical and cortico-cortical drives can produce the FC-ERP, similar to what has been shown for primary sensory cortices. We used this model of the FC-ERP to examine likely circuit-mechanisms underlying FC-ERP features that distinguish between successful and failed action-stopping. We also tested their adherence to the predictions of the horse-race model of the SST, with specific hypotheses motivated by theoretical links between the P3 and Stop process. These simulations revealed that a difference in P3 onset between successful and failed Stops is most likely due to a later arrival of thalamocortical drive in failed Stops, rather than, for example, a difference in effective strength of the input. In contrast, the same model predicted that early thalamocortical drives underpinning the P2 and N2 differed in both strength and timing across stopping accuracy conditions. Overall, this model generates novel testable predictions of the thalamocortical dynamics underlying FC-ERP generation during action-stopping. Moreover, it provides a detailed cellular and circuit-level interpretation that supports links between these macroscale signatures and predictions of the behavioral race model.

A causal role for the human subthalamic nucleus in non-selective cortico-motor inhibition.

Common cortico-basal ganglia models of motor control suggest a key role for the subthalamic nucleus (STN) in motor inhibition.1-3 In particular, when already-initiated actions have to be suddenly stopped, the STN is purportedly recruited via a hyperdirect pathway to net inhibit the cortico-motor system in a broad, non-selective fashion.4 Indeed, the suppression of cortico-spinal excitability (CSE) during rapid action stopping extends beyond the stopped muscle and affects even task-irrelevant motor representations.5,6 Although such non-selective CSE suppression has long been attributed to the broad inhibitory influence of STN on the motor system, causal evidence for this association is hitherto lacking. Here, 20 Parkinson's disease patients treated with STN deep-brain stimulation (DBS) and 20 matched healthy controls performed a verbal stop-signal task while CSE was measured from a task-unrelated hand muscle. DBS allowed a causal manipulation of STN, while CSE was measured using transcranial magnetic stimulation (TMS) over primary motor cortex and concurrent electromyography. In patients OFF-DBS and controls, the CSE of the hand was non-selectively suppressed when the verbal response was successfully stopped. Crucially, this effect disappeared when STN was disrupted via DBS in the patient group. Using this unique combination of DBS and TMS during human behavior, the current study provides first causal evidence that STN is likely involved in non-selectively suppressing the physiological excitability of the cortico-motor system during action stopping. This confirms a core prediction of long-held cortico-basal ganglia circuit models of movement. The absence of cortico-motor inhibition during STN-DBS may also provide potential insights into the common side effects of STN-DBS, such as increased impulsivity.7-11.

Cortico-subcortical ß burst dynamics underlying movement cancellation in humans.

Dominant neuroanatomical models hold that humans regulate their movements via loop-like cortico-subcortical networks, which include the subthalamic nucleus (STN), motor thalamus, and sensorimotor cortex (SMC). Inhibitory commands across these networks are purportedly sent via transient, burst-like signals in the ß frequency (15-29 Hz). However, since human depth-recording studies are typically limited to one recording site, direct evidence for this proposition is hitherto lacking. Here, we present simultaneous multi-site recordings from SMC and either STN or motor thalamus in humans performing the stop-signal task. In line with their purported function as inhibitory signals, subcortical ß-bursts were increased on successful stop-trials. STN bursts in particular were followed within 50 ms by increased ß-bursting over SMC. Moreover, between-site comparisons (including in a patient with simultaneous recordings from SMC, thalamus, and STN) confirmed that ß-bursts in STN temporally precede thalamic ß-bursts. This highly unique set of recordings provides empirical evidence for the role of ß-bursts in conveying inhibitory commands along long-proposed cortico-subcortical networks underlying movement regulation in humans.

The Pause-then-Cancel model of human action-stopping: Theoretical considerations and empirical evidence.

The ability to stop already-initiated actions is a key cognitive control ability. Recent work on human action-stopping has been dominated by two controversial debates. First, the contributions (and neural signatures) of attentional orienting and motor inhibition after stop-signals are near-impossible to disentangle. Second, the timing of purportedly inhibitory (neuro)physiological activity after stop-signals has called into question which neural signatures reflect processes that actually contribute to action-stopping. Here, we propose that a two-stage model of action-stopping - proposed by Schmidt and Berke (2017) based on subcortical rodent recordings - may resolve these controversies. Translating this model to humans, we first argue that attentional orienting and motor inhibition are inseparable because orienting to salient events like stop-signals automatically invokes broad motor inhibition, reflecting a fast-acting, ubiquitous Pause process. We then argue that inhibitory signatures after stop-signals differ in latency because they map onto two sequential stages: the salience-related Pause and a slower, stop-specific Cancel process. We formulate the model, discuss recent supporting evidence in humans, and interpret existing data within its context.

Non-selective inhibition of the motor system following unexpected and expected infrequent events.

Motor inhibition is a key control mechanism that allows humans to rapidly adapt their actions in response to environmental events. One of the hallmark signatures of rapidly exerted, reactive motor inhibition is the non-selective suppression of cortico-spinal excitability (CSE): unexpected sensory stimuli lead to a suppression of CSE across the entire motor system, even in muscles that are inactive. Theories suggest that this reflects a fast, automatic, and broad engagement of inhibitory control, which facilitates behavioral adaptations to unexpected changes in the sensory environment. However, it is an open question whether such non-selective CSE suppression is truly due to the unexpected nature of the sensory event, or whether it is sufficient for an event to be merely infrequent (but not unexpected). Here, we report data from two experiments in which human subjects experienced both unexpected and expected infrequent events during a two-alternative forced-choice reaction time task while CSE was measured from a task-unrelated muscle. We found that expected infrequent events can indeed produce non-selective CSE suppression-but only when they occur during movement initiation. In contrast, unexpected infrequent events produce non-selective CSE suppression relative to frequent, expected events even in the absence of movement initiation. Moreover, CSE suppression due to unexpected events occurs at shorter latencies compared to expected infrequent events. These findings demonstrate that unexpectedness and stimulus infrequency have qualitatively different suppressive effects on the motor system. They also have key implications for studies that seek to disentangle neural and psychological processes related to motor inhibition and stimulus detection.