Action Cancellation Research Articles

The role of 5-HT in response inhibition and re-engagement

In animal and human research, the neurotransmitter serotonin (5-HT) has been implicated in inhibitory control. Using functional magnetic resonance imaging (fMRI), the present study investigated the acute effects of pharmacological modulation of the serotonergic system on brain activation during response inhibition and re-engagement in healthy human volunteers. In a randomized double-blind placebo-controlled cross-over design 14 men received either a single oral dose of the selective serotonin reuptake inhibitor (SSRI) escitalopram (10mg) or a placebo. At the time of the expected plasma peak concentration, participants performed a stop–change task during fMRI. Escitalopram did not affect behavioural performance, since the main effect did not reveal significant differences between reaction times of go-, stop- or change-trials. During successful response inhibition, escitalopram, however, was associated with enhanced brain activation in right prefrontal cortex, right supplementary/pre-motor and bilateral cingulate cortex, and subcortical regions. During inhibition failures, escitalopram also modulated a broad network of brain regions, including anterior cingulate, right parietal cortex, right orbitofrontal cortex, and areas in right temporal cortex and subcortical regions. During response re-engagement escitalopram increased brain activation in right inferior frontal gyrus and precuneus as well as in left middle temporal gyrus. The results implicate the involvement of 5-HT in neural regulation of response inhibition and re-engagement. This study also provides evidence that 5-HT affects both action restraint and action cancellation through modulation of activation of brain areas. The results support the view for a fronto-striatal circuitry for response inhibition in conjunction with serotonin.

A Novel Translational Assay of Response Inhibition and Impulsivity: Effects of Prefrontal Cortex Lesions, Drugs Used in ADHD, and Serotonin 2C Receptor Antagonism

Animal models are making an increasing contribution to our understanding of the psychology and brain mechanisms underlying behavioral inhibition and impulsivity. The aim here was to develop, for the first time, a mouse analog of the stop-signal reaction time task with high translational validity in order to be able to exploit this species in genetic and molecular investigations of impulsive behaviors. Cohorts of mice were trained to nose-poke to presentations of visual stimuli. Control of responding was manipulated by altering the onset of an auditory 'stop-signal' during the go response. The anticipated systematic changes in action cancellation were observed as stopping was made more difficult by placing the stop-signal closer to the execution of the action. Excitotoxic lesions of medial prefrontal cortex resulted in impaired stopping, while the clinically effective drugs methylphenidate and atomoxetine enhanced stopping abilities. The specific 5-HT2C receptor antagonist SB242084 also led to enhanced response control in this task. We conclude that stop-signal reaction time task performance can be successfully modeled in mice and is sensitive to prefrontal cortex dysfunction and drug treatments in a qualitatively similar manner to humans and previous rat models. Additionally, using this model we show novel and highly discrete effects of 5-HT2C receptor antagonism that suggest manipulation of 5-HT2C receptor function may be of use in correcting maladaptive impulsive behaviors and provide further evidence for dissociable contributions of serotonergic transmission to response control.

Dopamine D2 Receptor Modulation of Human Response Inhibition and Error Awareness

Response inhibition, comprising action cancellation and action restraint, and error awareness are executive functions of considerable clinical relevance to neuropsychiatric disorders. Nevertheless, our understanding of their underlying catecholamine mechanisms, particularly regarding dopamine, is limited. Here, we used the dopamine D2 agonist cabergoline to study its ability to improve inhibitory control and modulate awareness of performance errors. A randomized, double-blind, placebo-controlled, crossover design with a single dose of cabergoline (1.25 mg) and placebo (dextrose) was employed in 25 healthy participants. They each performed the stop-signal task, a well-validated measure of action cancellation, and the Error Awareness Task, a go/no-go measure of action restraint and error awareness, under each drug condition. Cabergoline was able to selectively reduce stop-signal RT, compared with placebo, indicative of enhanced action cancellation (p < .05). This enhancement occurred without concomitant changes in overall response speed or RT variability and was not seen for errors of commission on the Error Awareness Task. Awareness of performance errors on the go/no-go task was, however, significantly improved by cabergoline compared with placebo (p < .05). Our results contribute to growing evidence for the dopaminergic control of distinct aspects of human executive ability, namely, action cancellation and error awareness. The findings may aid the development of new, or the repurposing of existing, pharmacotherapy that targets the cognitive dysfunction of psychiatric and neurological disorders. They also provide further evidence that specific cognitive paradigms have correspondingly specific neurochemical bases.

Disentangling common and specific neural subprocesses of response inhibition

Response inhibition is disturbed in several disorders sharing impulse control deficits as a core symptom. Since response inhibition is a cognitively and neurally multifaceted function which has been shown to rely on differing neural subprocesses and neurotransmitter systems, further differentiation to define neurophysiological endophenotypes is essential. Response inhibition may involve at least three separable cognitive subcomponents, i.e. interference inhibition, action withholding, and action cancelation. Here, we introduce a novel paradigm - the Hybrid Response Inhibition task - to disentangle interference inhibition, action withholding and action cancelation and their neural subprocesses within one task setting during functional magnetic resonance imaging (fMRI). To validate the novel task, results were compared to a battery of separate, standard response inhibition tasks independently capturing these subcomponents and subprocesses. Across all subcomponents, mutual activation was present in the right inferior frontal cortex (rIFC), pre-supplementary motor area (pre-SMA) and parietal regions. Interference inhibition revealed stronger activation in pre-motor and parietal regions. Action cancelation resulted in stronger activation in fronto-striatal regions. Our results show that all subcomponents share a common neural network and thus all constitute different subprocesses of response inhibition. Subprocesses, however, differ to the degree of regional involvement: interference inhibition relies more pronouncedly on a fronto-parietal-pre-motor network suggesting its close relation to response selection processes. Action cancelation, in turn, is more strongly associated with the fronto-striatal pathway implicating it as a late subcomponent of response inhibition. The new paradigm reliably captures three putatively subsequent subprocesses of response inhibition and might be a promising tool to differentially assess disturbed neural networks in disorders showing impulse control deficits.

The role of the lateral prefrontal cortex in inhibitory motor control

Research on inhibitory motor control has implicated several prefrontal as well as subcortical and parietal regions in response inhibition. Whether prefrontal regions are critical for inhibition, attention or task-set representation is still under debate. We investigated the influence of the lateral prefrontal cortex (PFC) in a response inhibition task by using cognitive electrophysiology in prefrontal lesion patients. Patients and age- and education-matched controls performed in a visual Stop-signal task featuring lateralized stimuli, designed to challenge either the intact or lesioned hemisphere. Participants also underwent a purely behavioral Go/Nogo task, which included a manipulation of inhibition difficulty (blocks with 50 vs. 80% go-trials) and a Change-signal task that required switching to an alternative response. Patients and controls did not differ in their inhibitory speed (stop-signal and change-signal reaction time, SSRT and CSRT), but patients made more errors in the Go/Nogo task and showed more variable performance. The behavioral data stress the role of the PFC in maintaining inhibitory control but not in actual inhibition. These results support a dissociation between action cancellation and PFC-dependent action restraint. Laplacian transformed event-related potentials (ERPs) revealed reduced parietal activity in PFC patients in response to the stop-signals, and increased frontal activity over the intact hemisphere. This electrophysiological finding supports altered PFC-dependent visual processing of the stop-signal in parietal areas and compensatory activity in the intact frontal cortex. No group differences were found in the mu and beta decrease as measures of response preparation and inhibition at electrodes over sensorimotor cortex. Taken together, the data provide evidence for a central role of the lateral PFC in attentional control in the context of response inhibition.

Neural correlates of interference inhibition, action withholding and action cancelation in adult ADHD

Attention-Deficit/Hyperactivity Disorder (ADHD) is marked by inhibitory and attentional deficits which can persist into adulthood. Those deficits have been associated with dysfunctional fronto-striatal and fronto-parietal circuits. The present study sought to delineate neural correlates of component specific inhibitory deficits in adult ADHD using functional magnetic resonance imaging (fMRI). 20 adult ADHD patients and 24 matched healthy controls were included. Brain activation was assessed during three stages of behavioral inhibition, i.e. interference inhibition (Simon task), action withholding (Go/no-go task) and action cancelation (Stop-signal task). Behaviorally, ADHD patients were affected in all tasks. Impaired interference inhibition was associated with hypoactivation in parietal and medial frontal regions. During action withholding and cancelation ADHD patients displayed hypoactivation in a fronto-striatal network. These findings support the notion of at least two disturbed neural circuits in ADHD differentially associated with deficits in separate inhibitory subcomponents. Thereby, deficits in inhibitory subcomponents which are closely connected to response interference were related to hypofunction in more attention related circuits, while stopping related deficits were rather associated with hypofunction in inhibitory circuits.

Transcranial Magnetic Stimulation Reveals Dissociable Mechanisms for Global Versus Selective Corticomotor Suppression Underlying the Stopping of Action

Stopping an initiated response is an essential function, investigated in many studies with go/no-go and stop-signal paradigms. These standard tests require rapid action cancellation. This appears to be achieved by a suppression mechanism that has "global" effects on corticomotor excitability (i.e., affecting task-irrelevant muscles). By contrast, stopping action in everyday life may require selectivity (i.e., targeting a specific response tendency without affecting concurrent action). We hypothesized that while standard stopping engages global suppression, behaviorally selective stopping engages a selective suppression mechanism. Accordingly, we measured corticomotor excitability of the task-irrelevant leg using transcranial magnetic stimulation while subjects stopped the hand. Experiment 1 showed that for standard (i.e., nonselective) stopping, the task-irrelevant leg was suppressed. Experiment 2 showed that for behaviorally selective stopping, there was no mean leg suppression. Experiment 3 directly compared behaviorally nonselective and selective stopping. Leg suppression occurred only in the behaviorally nonselective condition. These results argue that global and selective suppression mechanisms are dissociable. Participants may use a global suppression mechanism when speed is stressed; however, they may recruit a more selective suppression mechanism when selective stopping is behaviorally necessary and preparatory information is available. We predict that different fronto-basal-ganglia pathways underpin these different suppression mechanisms.

A New HTN Planning Framework for Agents in Dynamic Environments

In a dynamic environment, even if an agent makes a plan to obtain a goal, the environment might change while the agent is executing the plan. In that case, the plan, which was initially valid when it was made, might later become invalid. Furthermore, in the process of replanning, it is necessary to take into account the side effects of actions already executed. Nowadays, HTN planning is becoming popular among agent researchers because its task decomposition algorithm is efficient and suitable for joint planning in multi-agent systems. However, the dynamic replanning algorithm of HTN planning has not yet been established. In order to solve this problem, we have previously presented an agent life cycle that integrates HTN planning, action execution, knowledge updates, and plan modification. In that agent life cycle, the plans are always kept valid according to the most recent knowledge and situation. However, when one plan does not work and the agent starts using an alternative plan, it sometimes undoes some actions that do not have to be undone. The source of this problem lies in the need to have total-order plans. In other words, all the actions have to be sequentially ordered even when the order is not important in some parts of the plan. This paper extends our previous agent life cycle and presents new ways to avoid unnecessary action cancellation. This enables the agent to handle partial-order plans and to make use of two kinds of undoing actions: sequential undoing actions and concurrent undoing actions.

Bayesian equilibrium in double auctions populated by biased heuristic traders

We use computer simulation to examine three asset markets with imperfect information. In processing imperfect information, traders in the three markets are bayesian, empirical bayesian, and heuristic (representativeness and anchor-and-adjust) respectively. All three converge to the same bayesian equilibrium — although the latter two converge more slowly — without profit maximization, natural selection, arbitrage, or mutual cancellation of random actions. The results support Becker (1962) and Simon (1973) in that the rationality of the market emerges as a consequence of the market structure, and not from the rationality of individuals.

AN ELECTRON MICROSCOPIC STUDY OF A CASE OF DERMATOMYOSITIS.

<h3>Abstract</h3> ADHD is a neurodevelopmental disorder associated with significant morbidity and mortality that affects 5% of children, adolescents and adults worldwide. Pharmacological and behavioral therapies exist, but critical symptoms such as dysexecutive deficits remain unaffected. In this randomized, placebo-controlled, double-blind, cross-over study we assess the cognitive and physiological effects of tDCS in adult ADHD patients in order to understand (1) the role of DLPFC laterality in ADHD dysexecutive deficits, (2) the physiological dynamics sustaining the modulation of executive function by tDCS, and (3) the impact of state-dependent dynamics of tDCS effect. The participants consisted of a random sample of 40 adult patients with a primary diagnosis of ADHD. Each patient performed three experimental sessions in which they received 30 minutes of 2mA tDCS stimulation targeting the left DLPFC (anodal F3, cathodal Fp2), the right DLPFC (anodal F4, cathodal Fp1) and Sham. Before and after each session, half of the patients completed the Flanker task (EFT) and the other half performed the Stop Signal Task (SST), while we assessed cognitive (reaction time, accuracy) and neurophysiological measures (EEG Event-Related-Potentials). Results show that anodal tDCS to the left DLPFC modulated cognitive (reaction time) and physiological measures (P300 amplitude) in the Flanker task in a state-dependent manner, but there were no significant effects in the Stop Signal Reaction Time of the SST. We interpret these results as an improvement in interference cognitive control (captured by the EFT) but not in action cancellation (assessed by the SST), supporting the hypothesis of the existence of different impulsivity constructs with overlapping but distinct anatomical substrates and therapeutic strategies. We conclude that anodal tDCS over the left DLPFC using a simple bipolar montage has pro-cognitive effects in dysexecutive patients with ADHD associated with the modulation of physiological signatures of cognitive control (i.e. treatment target), supporting specific hypotheses and strategies for neuromodulation treatment development under an experimental therapeutics framework aiming to link target engagement (cognitive and physiological) with clinical benefit. In addition, we also provide empirical evidence supporting the value of the P200, N200 and P300 as cross-sectional biomarkers of cognitive performance across tasks. Last, we provide mechanistic support for the state-dependent nature of the effects of tDCS, highlighting the importance of controlling the neural states before and during stimulation as a relevant therapeutic strategy.