Elsevier

NeuroImage

Volume 41, Issue 4, 15 July 2008, Pages 1352-1363
NeuroImage

Subcortical processes of motor response inhibition during a stop signal task

https://doi.org/10.1016/j.neuroimage.2008.04.023Get rights and content

Abstract

Previous studies have delineated the neural processes of motor response inhibition during a stop signal task, with most reports focusing on the cortical mechanisms. A recent study highlighted the importance of subcortical processes during stop signal inhibition in 13 individuals and suggested that the subthalamic nucleus (STN) may play a role in blocking response execution (Aron and Poldrack, 2006. Cortical and subcortical contributions to Stop signal response inhibition: role of the subthalamic nucleus. J Neurosci 26, 2424–2433). Here in a functional magnetic resonance imaging (fMRI) study we replicated the finding of greater activation in the STN during stop (success or error) trials, compared to go trials, in a larger sample of subjects (n = 30). However, since a contrast between stop and go trials involved processes that could be distinguished from response inhibition, the role of subthalamic activity during stop signal inhibition remained to be specified. To this end we followed an alternative strategy to isolate the neural correlates of response inhibition (Li et al., 2006a. Imaging response inhibition in a stop signal task —– neural correlates independent of signal monitoring and post-response processing. J Neurosci 26, 186–192). We compared individuals with short and long stop signal reaction time (SSRT) as computed by the horse race model. The two groups of subjects did not differ in any other aspects of stop signal performance. We showed greater activity in the short than the long SSRT group in the caudate head during stop successes, as compared to stop errors. Caudate activity was positively correlated with medial prefrontal activity previously shown to mediate stop signal inhibition. Conversely, bilateral thalamic nuclei and other parts of the basal ganglia, including the STN, showed greater activation in subjects with long than short SSRT. Thus, fMRI delineated contrasting roles of the prefrontal-caudate and striato-thalamic activities in mediating motor response inhibition.

Introduction

Response inhibition allows flexible motor acts in changing environment. The stop signal task (SST) has been widely used to investigate the behavioral and neural processes of motor response inhibition (Logan, 1994, Logan and Cowan, 1984). In the SST, there are two different types of trials: “go” and “stop”. In the go trials, participants are required to respond to an imperative stimulus within a time window and, because the majority of the trials are go trials, they set up a prepotent response tendency. In the stop trials, an additional stop signal instructs participants to withhold their response. The rationale is that, when response inhibition is in place, participants are able to stop upon seeing the stop signal, resulting in a stop success. However, successful performance in the SST depends on a number of other cognitive processes in addition to response inhibition. For instance, one needs to monitor for the stop signal in order to initiate the inhibitory process in time to offset the prepotent tendency to respond during stop trials. Moment-by-moment lapses in attention as can occur when one is under-motivated or distracted make one prone to stop errors. Furthermore, because go trials appear more frequently than stop trials, an “impulsive” thought that no stop signal will follow the go signal leads to the execution of a response without a concurrent process of outcome monitoring. These psychological processes influence stop signal performance but do not necessarily reflect one's capacity of response inhibition (Li et al., 2006a).

Logan and colleagues have developed algorithms to derive a reliable measure of response inhibition, independent of these psychological variables (Logan, 1994, Logan and Cowan, 1984). For instance, with a tracking procedure in which the time delay between the stop and go signals (stop signal delay or SSD) varied trial by trial according to participant's performance, investigators can estimate the stop signal reaction time (SSRT) – a counterpart of the go trial RT – on the basis of a horse race model (Logan, 1994). Recent work that takes into account the interaction between go and stop processes in the race model further solidifies the use of SSRT as an index of response inhibition function (Boucher et al., 2007).

Previous neuroimaging studies employing the SST have examined the cortical processes of response inhibition (Aron and Poldrack, 2006, Li et al., 2006a, Liddle et al., 2001, Rubia et al., 2003, Rubia et al., 2005). Of critical interest are the different paradigms and contrasts investigators have used to isolate response inhibition. Because fMRI studies employing a block design were vulnerable to a number of important confounds (Aron and Poldrack, 2005), we focused the discussions on event-related paradigms. For instance, using a tracking procedure and contrasting brain activations associated with stop success (SS) and stop error (SE) trials, Rubia and colleagues observed greater activation in the inferior frontal cortices during SS, compared to SE, trials (Rubia et al., 2003, Rubia et al., 2005). However, as mentioned in the above, this contrast did not control for differences in signal monitoring, post-response processing (as, for instance, SS and SE trials are each subjectively rewarding and frustrating), and motor-related processes. Successful performance in the SST requires sustained attention and constant monitoring for the stop signal. Lapses in attention or failures in monitoring cause inhibition failures, for example, when one responds to the go signal, assuming no stop signal will follow. Therefore, by contrasting successful and failed inhibitions, one might simply be isolating activations related to such signal monitoring process (Li et al., 2006a).

Other investigators compared stop and go trials to isolate the neural processes of stop signal inhibition (Aron and Poldrack, 2006, Chevrier et al., 2007, Liddle et al., 2001, Pliszka et al., 2006). A rationale for this contrast perhaps is that the stop but not go process involves response inhibition. Compared to go trials, however, stop trials evoked more complicated perceptual signal processing. The visual/auditory processing of the stop signal admittedly is the starting point of a series of processes leading to response inhibition but it is not identical to response inhibition. Furthermore, response inhibition is not invariably evoked during stop trials, and subjects succeed or fail in inhibitions depending on whether this capacity is in place. Comparing stop and go trials without distinguishing stop success and error seems to be inconsistent with the underlying rationale of the SST. Thus, Curtis et al. observed greater activation in the frontal eye field during stop, compared to go, trials in an oculomotor countermanding task, and suggested that this may reflect concurrent activation of the go (saccade) and stop (fixation) motor processes within this brain region (Curtis et al., 2005). Without showing differences between successful and failed inhibitions, the activity in frontal eye field falls short of addressing the process of response inhibition and determining the trial outcome.

Subcortical structures and the basal ganglia, in particular, have been implicated in the regulation of both simple and complex motor acts (David et al., 2005, DeLong, 2000, Graybiel, 2005, Hikosaka, 2007, Romanelli et al., 2005 Seger, 2006, Tan et al., 2006). Dysfunction in the circuitry involving these subcortical structures has been implicated in a number of neurological conditions, including Parkinson's disease and attention deficit hyperactivity disorder (Bevan et al., 2006, DeLong and Wichmann, 2007, Mehler-Wex et al., 2006, Robbins, 2007). Among the subcortical structures, the subthalamic nucleus (STN) has received much attention because of its role in the pathogenesis and treatment of Parkinson's disease (Benabid, 2003, Bevan et al., 2006, Breit et al., 2004, Grafton et al., 2006, Hamani et al., 2005, Perlmutter and Mink, 2006). Deep brain stimulation (DBS) of the STN appeared to alleviate dyskinesia and other motor symptoms in patients with Parkinson's disease (Breit et al., 2004, Grafton et al., 2006, Hamani et al., 2005, Perlmutter and Mink, 2006). Although a reduction of excessive inhibitory activity in the STN may mediate the treatment effects, the therapeutic mechanisms of DBS remain to be elucidated. It would thus be of great interest to further explore the role of the STN and other subcortical processes in motor response inhibition in an imaging setting.

A recent study investigated the effects of DBS on the performance of patients with Parkinson's disease during a choice SST and a go/no-go task (van den Wildenberg et al., 2006). The results showed that DBS of the STN was associated with enhanced inhibitory control, as indicated by a shorter SSRT. Interestingly, the stimulation also improved the choice go trial RT during the SST but did not affect the simple go trial RT during the go/no-go task. Thus, it appears that the STN plays a role not only in inhibiting but also in generating a motor response (van den Wildenberg et al., 2006). Another recent experiment employed fMRI to examine the cortical and subcortical mechanisms of response inhibition during a SST (Aron and Poldrack, 2006). Testing the hypothesis that the STN suppresses the “direct” fronto-striatal pathway activated by response initiation (the “go” process), these investigators showed greater activation in the STN during stop trials (both stop successes and errors), compared to go trials (Aron and Poldrack, 2006). Furthermore, they demonstrated greater activation in the STN in subjects with short, compared to those with long, SSRT (though it was not clear whether the two groups differed significantly in SSRT). Overall, these results suggest a role of the STN in stop signal performance. In particular, the latter finding of SSRT-associated activity in the STN could indicate a more specific role of the STN in motor response inhibition, as described by the horse race model.

Here we aimed to examine thalamic and basal ganglia activities that may mediate stop signal inhibition, as computed by the race model. Our earlier work demonstrated that men and women may show important differences in the neural processes underlying stop signal performance (Li et al., 2006b); thus, we focused here on the results obtained in a group of 30 adult men subjects. We contrasted SS versus SE for individual subjects to account for stimulus condition between trial types. In random effect analysis, we contrasted short versus long SSRT groups of individuals who are identical in all other aspects of stop signal performance including stop success rate, thus accounting for the extent of attentional monitoring, in order to isolate the neural correlates of response inhibition (Logan et al., 1994). The regions of interest (ROIs) included bilateral caudate nucleus, putamen, pallidum, and STN. Thus, these ROIs broadly encompass the subcortical elements of the cortical-basal ganglia-thalamic loop widely implicated in motor control (DeLong, 1990, DeLong, 2000). We broadly hypothesized that these structures demonstrate different activity between individuals with short and long SSRT. Specifically, greater STN activity in the short, as compared to the long, SSRT group would replicate the findings of Aron and Poldrack, 2006. On the other hand, greater STN activity in the long, as compared to the short, SSRT group would be consistent with over-activity of the basal ganglia circuitry in patients with Parkinson's disease, who are known to be impaired in flexible behavioral performance including showing prolonged SSRT in the stop signal task (Gauggel et al., 2004).

Section snippets

Subjects and behavioral task

Thirty male adults (22–45 years of age, all right-handed and using their right thumb to respond) were paid to participate in the study. All subjects signed a written consent after details of the study were explained, in accordance to institute guidelines and procedures approved by the Yale Human Investigation Committee.

We employed a simple reaction time task in this stop signal paradigm (Li et al., 2006a, Logan and Cowan, 1984; Fig. 1). There were two trial types: “go” and “stop”, randomly

Stop signal performance

Table 1 shows the results of behavioral performance, separately for the subjects with short and long SSRT, grouped with a median split. Note that our subjects succeeded in approximately 51% of the stop trials, suggesting the success of the tracking procedure. The median go trial RT was indistinguishable between the four sessions (session 1 through 4: 547 ± 137; 611 ± 149; 597 ± 146; 591 ± 141 ms; p = 0.351, ANOVA). Furthermore, for all 30 subjects the RT and SSD was linearly correlated for stop trials

Caudate nucleus and cognitive–motor control

The caudate head shows greater activation in association with short SSRT, and the extent of its activation is positively correlated with activity in the pre-supplementary motor area (pre-SMA), a cortical structure that have been implicated in cognitive control and response planning and selection (Boecker et al., 1998, Boecker et al., 2008, Brass and Haggard, 2007, de Jong and Paans, 2007, Isoda and Hikosaka, 2007, Lau et al., 2004, Li et al., 2006a, Mueller et al., 2007, Nachev et al., 2005,

Conclusion

To summarize, we demonstrated greater activity in the caudate nucleus in association with short SSRT. With its functional connections with the pre-SMA, we thus seem to have identified a cortico-striatal circuitry associated with expedient response inhibition. In contrast, the thalamus and other parts of the basal ganglia, including the STN, show greater activity in association with long SSRT, consistent with the idea that over-activity in the striato-thalamic circuitry might impair flexible

Acknowledgments

This study was supported by NIH grants R01-DA11077 (Sinha), P50-DA16556 (Sinha), K02-DA17232 (Sinha), and R03-DA022395 (Li). It was also supported by a research grant from the Alcoholic Beverage Medical Research Foundation (Li), and research grant (Li) from the Clinical Translational Science Award (NIH-UL1 RR024139) awarded to Yale University, a Physician Scientist training grant (K12-DA000167, Bruce Rounsaville) and P50-DA09241 (Bruce Rounsaville). This project was also funded in part by the

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