Brain pathways underlying Response Inhibition and Response Caution

Roles of the medial frontal cortices in the selection, storage and retrieval of response tactics in a voluntary arm-reaching task

The Stop Signal Task (SST), a commonly used measure of response inhibition, uses standard psychophysical methods to gain an estimate of the time needed to withhold a prepotent response. Under some circumstances, conventional forms of the SST are impractical to use because of the large number of trials necessary to gain a reliable estimate of the speed of inhibition. Here we applied to the SST an adaptive method for estimating psychometric parameters that can find reliable threshold estimates over a relatively small number of trials. The Ψ adaptive staircase, which uses a Bayesian algorithm to find the most likely parameters of a psychophysical function, was used to estimate the critical stop signal delay at which the probability of successful response inhibition equals 0.5. Using computational modeling and adult participants, estimates of stop signal reaction time (SSRT) based on the Ψ staircase were compared to estimates using the method of constant stimuli and a standard staircase method of adjustment. Results demonstrate that a reliable estimate of SSRT can be gained very quickly (20–30 stop trials), making the method very useful for testing populations that cannot maintain concentration for long periods or for rapidly obtaining multiple SSRT estimates from healthy adult participants.

Inhibitory control is a key executive function and has been studied extensively using the stop signal task. By applying a simple race model that posits an independent race between a GO process responsible for initiation of responses and a STOP process responsible for inhibition of responses, one can estimate how long it takes an individual to inhibit an ongoing response, the stop signal reaction time. Here, we examined how stop signal reaction time can be affected by working memory. Participants engaged in a dual task; they completed a stop signal task under low and high working memory load conditions. Working memory capacity was also measured. We found that the STOP process was lengthened in the high, compared to the low, working memory load condition, as evidenced by differences in stop signal reaction time. The GO process was unaffected and working memory capacity could not account for differences across the load conditions. These results indicate that inhibitory control can be influenced by placing demands on working memory.

A lack of inhibitory control has been suggested to be the core deficit in attention-deficit/hyperactivity disorder (ADHD), especially in adults. This means that a primary deficit in inhibition mediates a cascade of secondary deficits in other executive functions, such as attention. Impaired stopping has been claimed to support the inhibition hypothesis. However, executive functions such as inhibition and attention are hard to disentangle. To use event-related potentials in adult patients with ADHD to show that impaired stopping is associated with abnormalities of attention. The stop signal task was presented to 24 adults with ADHD combined subtype and 24 controls. Stop event-related potentials are distorted by overlap from event-related potentials to other stimuli in close temporal proximity, but we applied a method (Adjar level 2) to effectively remove this overlap. In line with an inhibitory control deficit, the stop signal reaction time was longer in adults with ADHD (F(1,46) = 7.12, P<.01) whereas there was no significant difference for go stimulus reaction time. Overlap-free stop event-related potentials revealed smaller stop P3s in adults with ADHD (F(1,44) = 4.20, P<.05). In children with ADHD, this has been interpreted to reflect deficient inhibitory control. However, controls were also found to have larger early responses in the auditory cortex (N1) when stop signals resulted in successful stops, relative to failed stops, signifying increased attention (F(1,23) = 11.88, P<.01). This difference was completely absent in adults with ADHD. Disturbed attentional processing of the stop signal contributed to impaired stopping in adults with ADHD. This finding may have implications for treatment.

BackgroundA robust feature of sensorimotor synchronization (SMS) performance in finger tapping to an auditory pacing signal is the negative asynchrony of the tap with respect to the pacing signal. The Paillard–Fraisse hypothesis suggests that negative asynchrony is a result of inter-modal integration, in which the brain compares sensory information across two modalities (auditory and tactile). The current study compared the asynchronies of vocalizations and finger tapping in time to an auditory pacing signal. Our first hypothesis was that vocalizations have less negative asynchrony compared to finger tapping due to the requirement for sensory integration within only a single (auditory) modality (intra-modal integration). However, due to the different measurements for vocalizations and finger responses, interpreting the comparison between these two response modalities is problematic. To address this problem, we included stop signals in the synchronization task. The rationale for this manipulation was that stop signals would perturb synchronization more in the inter-modal compared to the intra-modal task. We hypothesized that the inclusion of stop signals induce proactive inhibition, which reduces negative asynchrony. We further hypothesized that any reduction in negative asynchrony occurs to a lesser degree for vocalization than for finger tapping.MethodA total of 30 participants took part in this study. We compared SMS in a single sensory modality (vocalizations (or auditory) to auditory pacing signal) to a dual sensory modality (fingers (or tactile) to auditory pacing signal). The task was combined with a stop signal task in which stop signals were relevant in some blocks and irrelevant in others. Response-to-pacing signal asynchronies and stop signal reaction times were compared across modalities and across the two types of stop signal blocks.ResultsIn the blocks where stopping was irrelevant, we found that vocalization (−61.47 ms) was more synchronous with the auditory pacing signal compared to finger tapping (−128.29 ms). In the blocks where stopping was relevant, stop signals induced proactive inhibition, shifting the response times later. However, proactive inhibition (26.11 ms) was less evident for vocalizations compared to finger tapping (58.06 ms).DiscussionThese results support the interpretation that relatively large negative asynchrony in finger tapping is a consequence of inter-modal integration, whereas smaller asynchrony is associated with intra-modal integration. This study also supports the interpretation that intra-modal integration is more sensitive to synchronization discrepancies compared to inter-modal integration.

Previous studies have shown cultural differences in the behavioral and neural processes of perspective taking and social emotional processing. It is less clear whether culture influences cognitive functions that do not explicitly involve face perception, group membership or social interactions. Here, we addressed this issue by imaging 29 Asians and 168 European Americans while they performed a stop signal task (SST)—a behavioral paradigm widely used to study cognitive control. In the SST participants responded to a frequent go signal and interrupted their response to an infrequent stop signal. Imaging data were processed by published routines implemented in Statistical Parametric Mapping. Behaviorally Asians and European Americans did not differ in SST performance measures, including the go and stop success rates, go and stop signal reaction time, and the sequential effect, an index of performance monitoring and behavioral adjustment. In a Bayesian model of the SST performance, we identified regional responses to stimulus prediction error (expecting go while encountering stop signal or vice versa) and showed that the dorsal anterior cingulate cortex (dACC) responded to Bayesian prediction error, a surprise signal. Importantly, compared to European Americans, Asians showed higher dACC response to prediction error in a voxelwise analysis examined at a corrected threshold. This finding suggested that, although an increased response to surprise did not impact behavioral performance, Asians appeared to exhibit higher arousal to a salient signal than European Americans, a process likely mediated by midbrain catecholaminergic system. This finding supports racial cultural differences in cognitive and affective processes that go beyond the domains of social emotions, and adds to a growing literature of cultural neuroscience.

Evidence from animal, clinical, and imaging studies suggests that the basal ganglia and their frontal connections mediate motor inhibition, but the role of dopamine remains unclear. The aim of our study was to investigate, for the first time, whether levodopa medication influences motor inhibition and conflict resolution on the conditional stop-signal reaction time task in patients with Parkinson's disease (PD) tested on or off their medication. Sixteen PD patients and 17 healthy controls performed the conditional stop-signal reaction time (SSRT) task, which requires inhibition of responses when a stop signal is presented on "critical" trials. Additionally, on "non-critical" trials, participants are instructed to ignore the stop signal and respond, thus generating conflict between motor inhibition and initiation; and conflict-induced slowing (CIS) on these "non-critical" trials. Levodopa medication did not significantly influence response initiation, inhibition (SSRT) or the measure of conflict resolution (CIS). Compared to healthy controls, PD patients showed significantly worse response initiation and inhibition both on and off their levodopa medication. Our results suggest that motor inhibition or conflict-induced slowing on the conditional stop-signal RT task are not altered by dopamine replacement in PD. This conclusion is consistent with evidence from animal studies and clinical pharmacological investigations suggesting a role for noradrenaline in motor inhibition and impulsivity.

Driving a car requires a complex combination of various cognitive functions (e.g., visual perception, motor control, decision making, and others), and deficits in any of these processes may compromise driving safety. Amongst these, executive functions such as inhibitory control, task switching, and decision-making are important, as they enable drivers to process information from their surroundings and respond appropriately to changing road conditions. Although previous research has focused on laboratory measures of individual executive functions, it remains unclear whether performance on such laboratory tests readily translates to actual on-the-road driving performance, especially since drivers' skill levels can vary widely, based on their driving frequency. To this end, we divided 30 participants into two categories based on their driving frequency (i.e., daily commuter vs. weekend only drivers), and we used three well-known executive functioning tasks (the stop signal task, Iowa gambling task or IGT, and a task-switching test) to see whether scores on these tasks predicted such driving performances and behaviors such as braking time, lane-keeping, speed limit violations, and inter-vehicle distance (e.g., in a driving simulator). Participants went through a follow-lead-car scenario in the driving simulator for 20minutes and then completed the three executive tasks. We found that stop signal reaction time (SSRT) best predicted driving performance, and remained predictive against driver distraction, as well as variabilities in driving frequency. The IGT predicted speed limit violations in high-frequency drivers, whereas task-switching cost predicted lane keeping performance in low-frequency drivers. Together, these results highlight the importance of driving frequency when considering correlates between executive functions and driving performance and behavior. They also imply that executive tasks better predict driving performance in low-frequency (or inexperienced) drivers, while driver temperament (i.e., impulsiveness as indicated by IGT) better predicted driving performance in high-frequency (or experienced) drivers.

ObjectiveCluster analysis of spatio-temporal event-related potential (ERP) data is a promising tool for exploring the measurement time window of ERPs. However, even after preprocessing, the remaining noise can result in uncertain cluster maps followed by unreliable time windows while clustering via conventional clustering methods. MethodsWe designed an ensemble deep clustering pipeline to determine a reliable time window for the ERP of interest from temporal concatenated grand average ERP data. The proposed pipeline includes semi-supervised deep clustering methods initialized by consensus clustering and unsupervised deep clustering methods with end-to-end architectures. Ensemble clustering from those deep clusterings was used by the designed adaptive time window determination to estimate the time window. ResultsAfter applying simulated and real ERP data, our method successfully obtained the time window for identifying the P3 components (as the interest of both ERP studies) while additional noise (e.g., adding 20 dB to −5 dB white Gaussian noise) was added to the prepared data. ConclusionCompared to the state-of-the-art clustering methods, a superior clustering performance was yielded from both ERP data. Furthermore, more stable and precise time windows were elicited as the noise increased. SignificanceOur study provides a complementary understanding of identifying the cognitive process using deep clustering analysis to the existing studies. Our finding suggests that deep clustering can be used to identify the ERP of interest when the data is imperfect after preprocessing.

Pre-stimulus EEG effects related to response speed, task switching and upcoming response hand

The aim of this work is to further understanding into the biological bases of human executive control through an integration of neuropsychology,psychopharmacology and functional imaging. Executive control includes the prototypical executive functions of response inhibition and error awareness. Response inhibition can be further divided into action cancellation and action restraint, which were assayed with the stop signal (SST) and Error Awareness(EAT) tasks, respectively. The EAT, which is a modified go-no go paradigm, was also used to measure error awareness behaviour. Monoamine neurotransmitters, specifically dopamine, noradrenaline and serotonin, were modulated during task performance with acute doses of methylphenidate (a dopamine and noradrenaline reuptake inhibitor), atomoxetine (a noradrenaline reuptake inhibitor), citalopram (a serotonin reuptake inhibitor) and cabergoline (a D2 agonist). The pharmacoimaging correlates of task performance were also examined with functional magnetic resonance imaging (fMRI). All experiments adhered to a randomised, double blind, placebo-controlled, crossover design and were limited to 18-35 year old healthy right-handed male participants. In Chapter 1, twenty-four (24) participants received acute doses of methylphenidate (30mg), atomoxetine (60mg), citalopram (30mg) and placebo and performed the SST. Methylphenidate, but not atomoxetine or citalopram, led to a reduction in response time variability and stop-signal reaction time indicating enhanced action cancellation compared with the other drug conditions. This enhancement occurred without change to overall response speed suggesting that methylphenidate was modulating core response inhibition processes rather than simply augmenting overall processing speed. This result argued for the prominence of dopaminergic, rather than adrenergic or serotonergic, mechanisms in action cancellation. In Chapter 2, the pharmacoimaging correlates of action restraint aspect were explored. Twenty-seven (27) males received acute doses of methylphenidate(30mg), atomoxetine (60mg), citalopram (30mg) and placebo whilst undertaking the EAT during fMRI. No-go related BOLD activations were then correlated for each of the drug conditions. Although Inhibitory performance under methylphenidate was numerically superior to the other drug conditions,this difference did not achieve statistical significance. On fMRI, methylphenidate activated, versus placebo, the anterior cingulate cortex, right inferior frontal, left middle frontal, left angular and right superior temporal gyri and right caudate. Atomoxetine activated a broad network of cortical regions. Both methylphenidate and atomoxetine, but not citalopram, activated superior temporal, right inferior frontal and left middle frontal clusters. Citalopram only activated the left inferior occipital lobe. Taking each condition’s activations as functionally defined regions of interest, the specificity of no-go related activity was compared across the four conditions. Only methylphenidate demonstrated drug specific effects through increased activation of the anterior cingulate and decreased activation of the caudate. A direct comparison of methylphenidate and atomoxetine showed a similar recruitment in prefrontal regions but specific effects of methylphenidate in the anterior cingulate and caudate. This further supported the notion that dopaminergic processes were making a specific and dissociable contribution during response inhibition. In Chapter 3 the pharmacoimaging correlates of error awareness were examined using the EAT. This study examined the fMRI data obtained whilst testing the cohort described in Chapter 2. Methylphenidate, but not atomoxetine or citalopram, significantly improved error awareness behaviour during the EAT. Methylphenidate, versus the other drug conditions, was also associated with specific BOLD activation differences in the dorsal anterior cingulate cortex and inferior parietal lobe for errors made with versus without awareness. These findings suggested that dopaminergic, rather than noradrenergic or serotonergic, mechanisms might also be important during error awareness. Accordingly, the final experiment in this thesis sought to examine specific dopamine receptor mechanisms of executive control. In Chapter 4 the role of the D2 receptor during response inhibition and error awareness was explored. Twenty-five (25) males received acute doses of cabergoline (1.25mg) and placebo before undertaking the SST and EAT. During the SST cabergoline was able to selectively reduce stop signal reaction time without a concomitant effect on reaction time variability or overall response speed. Cabergoline was, however, unable to improve action restraint in the go no-go component of the EAT. This suggested a specific and dissociable role for the D2 receptor in the action cancellation but not action restraint, which was consistent with the findings of Chapters 1 and 2. Cabergoline was also able to enhance the conscious perception of errors during the EAT, suggesting D2 mechanisms during error awareness, which was supportive of the findings in Chapter 3. In summary, this series of experiments showed that dopaminergic, and potentially D2, mechanisms are specifically implicated in the neurobiology of human executive control. Further experiments with more specific D2 agents, combined imaging paradigms and refined task design would extend these findings.

Conflict anticipation in alcohol dependence — A model-based fMRI study of stop signal task

The ability to inhibit actions inappropriate for the context is essential for meeting the shifting demands of complex environments. The stop signal task (SST) has been used in many previous studies to examine the interactions between go and stop responses in a cognitively demanding task involving attention, conflict resolution, and motor plan selection. The current study uses a variant of the SST, in which the continue signal instructs participants to proceed with the go response they were preparing. Reaction times (RTs) on continue trials were bimodally distributed, suggesting that an aspect of inhibition was involved in at least some of the trials. We investigated whether the cognitive processes delaying the generation of a behavioural response on continue trials are the same as for stop trials. We found improvement of stop signal reaction times (SSRTs) following stop trials, but the decrease in continue signal reaction times (CSRTs) was not significant. No improvement in either SSRT or CSRT was found following continue trials, suggesting that activation of the processes delaying the response on continue trials is insufficient to drive subsequent adjustments in SSRT or CSRT. In addition, go RTs only slowed following stop trials. These effects may suggest the presence of a selective learning process, which requires that the initial inhibition captured by SSRT and CSRT be combined with recognition of the stop signal specifically to affect subsequent performance.

Response inhibition is a critical cognitive ability underlying executive control over reactions to external cues, or inner requirements. Previous studies suggest that high arousal negative emotions (e.g., anger or fear) could impair response inhibition in implicit emotional stop signal tasks (eSSTs). However, studies exploring how low arousal negative emotions (e.g., sadness) influence response inhibition remain sparse. In the current study, 20 female college students performed an explicit eSST to explore the influence of sadness on response inhibition and its neural mechanism. Participants are instructed to press a button to sad or neutral facial stimuli while inhibiting their response during the presentation of a stop signal. Results showed that compared with neutral stimuli, sad stimuli were related to increased stop signal reaction time (SSRT) (i.e., worse response inhibition). Compared with neutral condition, higher activation during sad condition was found within the right superior frontal gyrus (SFG), right insula, right middle cingulate cortex (MCC), bilateral superior temporal gyrus (STG), left lingual gyrus, and right motor cortex. These findings indicated that sadness, like other negative emotions, may impair response inhibition in an explicit way and highlight the explicit eSST as a new paradigm to investigate the subtle interaction between negative emotion processing and cognitive control.

Cognitive decline is a common feature of Parkinson’s disease, and many of these cognitive deficits fail to respond to dopaminergic therapy. Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy. Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition deficits. Restoring noradrenaline levels using the noradrenergic reuptake inhibitor atomoxetine can improve response inhibition in some patients with Parkinson’s disease, but there is considerable heterogeneity in treatment response. Accurately predicting the patients who would benefit from therapies targeting this neurotransmitter system remains a critical goal, in order to design the necessary clinical trials with stratified patient selection to establish the therapeutic potential of atomoxetine. Here, we test the hypothesis that integrity of the noradrenergic locus coeruleus explains the variation in improvement of response inhibition following atomoxetine. In a double-blind placebo-controlled randomised crossover design, 19 people with Parkinson’s disease completed an acute psychopharmacological challenge with 40 mg of oral atomoxetine or placebo. A stop-signal task was used to measure response inhibition, with stop-signal reaction times obtained through hierarchical Bayesian estimation of an ex-Gaussian race model. Twenty-six control subjects completed the same task without undergoing the drug manipulation. In a separate session, patients and controls underwent ultra-high field 7T imaging of the locus coeruleus using a neuromelanin-sensitive magnetisation transfer sequence. The principal result was that atomoxetine improved stop-signal reaction times in those patients with lower locus coeruleus integrity. This was in the context of a general impairment in response inhibition, as patients on placebo had longer stop-signal reaction times compared to controls. We also found that the caudal portion of the locus coeruleus showed the largest neuromelanin signal decrease in the patients compared to controls. Our results highlight a link between the integrity of the noradrenergic locus coeruleus and response inhibition in Parkinson’s disease patients. Furthermore, they demonstrate the importance of baseline noradrenergic state in determining the response to atomoxetine. We suggest that locus coeruleus neuromelanin imaging offers a marker of noradrenergic capacity that could be used to stratify patients in trials of noradrenergic therapy and to ultimately inform personalised treatment approaches.