We frequently guide our decisions about when and how to act based on the meanings of perceptual inputs: we might avoid treading on a flower, but not on a leaf. However, most research on response inhibition has used simple perceptual stimuli devoid of meaning. In two Go/No-Go experiments, we examined whether the neural mechanisms supporting response inhibition are influenced by the relevance of meaning to the decision, and by presentation modality (whether concepts were presented as words or images). In an on-line fMRI experiment, we found common regions for response inhibition across perceptual and conceptual decisions. These included the bilateral intraparietal sulcus and the right inferior frontal sulcus, whose neural responses have been linked to diverse cognitive demands in previous studies. In addition, we identified a cluster in ventral lateral occipital cortex that was sensitive to the modality of input, with a stronger response to No-Go than Go trials for meaningful images, compared to words with the same semantic content. In a second experiment, using resting-state fMRI, we explored how individual variation in the intrinsic connectivity of these activated regions related to variation in behavioural performance. Participants who showed stronger connectivity between common inhibition regions and limbic areas in medial temporal and subgenual anterior cingulate cortex were better at inhibition when this was driven by the meaning of the items. In addition, regions with a specific role in picture inhibition were more connected to a cluster in the thalamus/caudate for participants who were better at performing the picture task outside of the scanner. Together these studies indicate that the capacity to appropriately withhold action depends on interactions between common control regions, which are important across multiple types of input and decision, and other brain regions linked to specific inputs (i.e., visual features) or representations (e.g., memory).

Repeated intermittent exposure to psychostimulants, such as amphetamine, leads to a progressive enhancement of the drug's ability to increase both behavioral and brain neurochemical responses. The expression of these enhancements, known as sensitization, can be regulated by Pavlovian conditioned stimuli. Cues that are associated with drug experience can facilitate sensitization so that it only occurs in the presence of these stimuli (context-specific sensitization). In contrast, cues that are explicitly related to the absence of drugs (conditioned inhibitors) can prevent the expression of sensitization. We hypothesized that disrupting conditioned inhibition would enable amphetamine sensitization in new contexts. Using male Sprague Dawley rats and a two-context amphetamine conditioning procedure, we found that extinguishing amphetamine experience in one environment led to the loss of conditioned inhibition in a separate context. Thus, amphetamine-induced sensitized locomotion, as well as both enhanced dopamine and glutamate neurotransmission in the nucleus accumbens, were observed in a context where the drug was never experienced before. A similar loss of contextual control of sensitization was seen after using baclofen/muscimol microinjections to transiently inhibit the medial prefrontal cortex, basolateral amygdala, or ventral subiculum of the hippocampus. In other words, compared to control infusions, these intracranial injections of GABA-receptor agonists were able to block conditioned inhibitors from preventing the expression of sensitized locomotion. Together, these findings reveal the importance of conditioned inhibitors for regulating addiction-like behavior. The results suggest that dopaminergic and glutamatergic brain circuitry controls the context-specific expression of amphetamine sensitization.

The ability to inhibit responses under high stakes, or "incentivized inhibition," is critical for adaptive impulse control. While previous research indicates that right ventrolateral prefrontal cortical (VLPFC) activity plays a key role in response inhibition, less research has addressed how incentives might influence this circuit. By combining a novel behavioral task, functional magnetic resonance imaging (FMRI), and diffusion-weighted imaging (DWI), we targeted and characterized specific neural circuits that support incentivized inhibition. Behaviorally, large incentives enhanced responses to obtain money, but also reduced response inhibition. Functionally, activity in both right VLPFC and right anterior insula (AIns) predicted successful inhibition for high incentives. Structurally, characterization of a novel white-matter tract connecting the right AIns and VLPFC revealed an association of tract coherence with incentivized inhibition performance. Finally, individual differences in right VLPFC activity statistically mediated the association of right AIns-VLPFC tract coherence with incentivized inhibition performance. These multimodal findings bridge brain structure, brain function, and behavior to clarify how individuals can inhibit impulses, even in the face of high stakes.

Saccadic eye movements are often imprecise and result in an error between expected and actual retinal target location after the saccade. Repeated experience of this error produces changes in saccade amplitude to reduce the error and concomitant changes in apparent visual location. We investigated the relationship between these two plastic processes in a series of experiments. Following a recent paradigm of inhibition of saccadic adaptation, in which participants are instructed to look at the initial target position and to continue to look at that position even if the target were to move again, our participants nevertheless perceived a visual probe presented near the saccade target to be shifted in direction of the target error. The location percept of the target gradually shifted and diverged over time from the executed saccade. Our findings indicate that changes in perceived location can be the same even when changes in saccade amplitude differ according to instruction and can develop even when the amplitude of the saccades executed during the adaptation procedure does not change. There are two possible explanations for this divergence between the adaptation states of saccade amplitude and perceived location. Either the intrasaccadic target step might trigger updating of the association between pre- and post-saccadic target positions, causing the localization shift, or the saccade motor command adjusts together with the perceived location at a common adaptation site, downstream from which voluntary control is exerted upon the executed eye movement only.

In a task-switching paradigm, response repetition (RR) often produces costs in task-switch trials but smaller costs or even benefits in task-repeat trials. Response inhibition accounts consistently attribute negative RR effects to the inhibition of the previous response, but they have different views on this inhibition process. According to the task-specific inhibition hypothesis, the previous response is inhibited when the task-switch is called for; whereas according to the general inhibition hypothesis, the response was generally inhibited after the execution. The present study utilized the electroencephalographs (EEGs) to investigate the response inhibition in the task-switching paradigm, with lateralized upper-alpha and beta enhancements serving as indexes of response inhibition. In blocks with task preparation, a task cue during the response-stimulus interval (RSI) was used to indicate which task was required, and the blocks without task preparation served as the control condition. The result indicated that, during the cue-stimulus interval (CSI), lateralized upper-alpha enhancements appeared only in trials with task-switch preparation, supporting the task-specific inhibition hypothesis. By contrast, regardless of whether there was task preparation and which task to prepare, lateralized beta enhancements appeared during the RSI, which provided evidence for the general inhibition hypothesis. These results suggest the existence of two different response inhibition processes in the task-switching paradigm.

Cognitive processes are traditionally studied in individual settings, while the possible effect of the social context is ignored. The present study focuses on the social inhibition of return effect (SIOR; Welsh et al., 2005). According to it, observation of another person's action at a specific location initiates an inhibitory process in the observer at that location. The aim of the present study was to investigate which processes are influenced by the social context (e.g. action representation, attention, etc.) and whether this effect is elicited only in a social context. In a series of four experiments we examined the SIOR effect by developing a dyadic computerized task in which each participant, in turn, responded to a peripherally presented target in two successive trials. The first trial was performed after the other participant had responded and was designed to examine SIOR. The second trial was aimed at studying self-induced IOR. The first two experiments replicated and extended previous findings by demonstrating that information regarding the counterpart's response location was sufficient to produce SIOR. In the third experiment the participants performed the same task but without a counterpart so that SIOR was eliminated. The fourth experiment demonstrated that believing there is a co-actor is enough to elicit the SIOR effect. These findings suggest that knowing that a location was acted upon before by another person (by observation or by prior knowledge) is the minimal condition for the SIOR effect to be evoked.

The atypical PKC isoforms, PKMζ and PKCλ have been proposed as integral substrates of long-term memory (LTM). Inhibition of these isoforms has recently been demonstrated to be sufficient for impairing the expression and maintenance of long-term potentiation. Additionally, the pseudosubstrate inhibitor, zeta inhibitory peptide (ZIP), which effectively blocks PKMζ and PKCλ, has previously been shown to disrupt associative memory; very little is known about its effects on pathological nonassociative forms of memory related to addiction. The neural and molecular substrates of memory and addiction have recently been argued to overlap. Here, we used ZIP to disrupt PKMζ and PKCλ activity to examine their role in cocaine sensitization, a nonassociative, addiction-related memory argued to underlie the transition from casual to pathological drug use. We examined the effects of both continuous and acute administration of ZIP. Even a single application of ZIP blocked the development of sensitization; sustained inhibition using osmotic pumps produced an almost complete blockade of sensitization. Further, a single application of ZIP was shown to reduce membrane-bound AMPAR expression. These results demonstrate a novel, critical role for the atypical PKC isoforms in nonassociative memory and cocaine addiction.

Past studies have shown evidence of transfer of learning in action video games, less so in other types, e.g. strategy games. Further, the transfer of learning from games to inhibitory control has yet to be examined from the perspectives of time constraint and logic contradiction. We examined the effect of strategy games (puzzle, turn-based strategy 'TBS', and real-time strategy 'RTS') on inhibition (response inhibition and distractor inhibition) and cerebral hemispheric activation over 4 weeks. We predicted that compared to RTS, puzzle and TBS games would (1) improve response and distractor inhibition, and (2) increase cerebral hemispheric activation demonstrating increased inhibitory control. A total of 67 non-habitual video game players (Mage = 21.63 years old, SD = 2.12) played one of three games: puzzle (n = 19), TBS (n = 24) or RTS (n = 24) for 4 weeks on their smartphones. Participants completed three inhibition tasks, working memory (WM), and had their tympanic membrane temperature (TMT) taken from each ear before and after playing the games. Results showed that only the puzzle game group showed an improved response inhibition while controlling for WM. There were no significant changes in the distractor inhibition tasks. We also found that there was an increase in left TMT while playing RTS, suggesting the presence of increased impulsivity in RTS. Our findings suggest that puzzle games involving logical contradiction could improve response inhibition, showing potential as a tool for inhibition training.

A network of brain regions involving the ventral inferior frontal gyrus/anterior insula (vIFG/AI), presupplementary motor area (pre-SMA) and basal ganglia has been implicated in stopping impulsive, unwanted responses. However, whether this network plays an equal role in response inhibition under different sensorimotor contexts has not been tested systematically. Here, we conducted an fMRI experiment using the stop signal task, a sensorimotor task requiring occasional withholding of the planned response upon the presentation of a stop signal. We manipulated both the sensory modality of the stop signal (visual versus auditory) and the motor response modality (hand versus eye). Results showed that the vIFG/AI and the preSMA along with the right middle frontal gyrus were commonly activated in response inhibition across the various sensorimotor conditions. Our findings provide direct evidence for a common role of these frontal areas, but not striatal areas in response inhibition independent of the sensorimotor contexts. Nevertheless, these three frontal regions exhibited different activation patterns during successful and unsuccessful stopping. Together with the existing evidence, we suggest that the vIFG/AI is involved in the early stages of stopping such as triggering the stop process while the preSMA may play a role in regulating other cortical and subcortical regions involved in stopping.

The stop-signal paradigm has become ubiquitous in investigations of inhibitory control. Tasks inspired by the paradigm, referred to as stop-signal tasks, require participants to make responses on go trials and to inhibit those responses when presented with a stop-signal on stop trials. Currently, the most popular version of the stop-signal task is the 'choice-reaction' variant, where participants make choice responses, but must inhibit those responses when presented with a stop-signal. An alternative to the choice-reaction variant of the stop-signal task is the 'anticipated response inhibition' task. In anticipated response inhibition tasks, participants are required to make a planned response that coincides with a predictably timed event (such as lifting a finger from a computer key to stop a filling bar at a predefined target). Anticipated response inhibition tasks have some advantages over the more traditional choice-reaction stop-signal tasks and are becoming increasingly popular. However, currently, there are no openly available versions of the anticipated response inhibition task, limiting potential uptake. Here, we present an open-source, free, and ready-to-use version of the anticipated response inhibition task, which we refer to as the OSARI (the Open-Source Anticipated Response Inhibition) task.

The stop-signal paradigm, a primary experimental paradigm for understanding cognitive control and response inhibition, rests upon the theoretical foundation of race models, which assume that a go process races independently against a stop process that occurs after a stop-signal delay (SSD). We show that severe violations of this independence assumption at short SSDs occur systematically across a wide range of conditions, including fast and slow reaction times, auditory and visual stop signals, manual and saccadic responses, and especially in selective stopping. We also reanalyze existing data and show that conclusions can change when short SSDs are excluded. Last, we suggest experimental and analysis techniques to address this violation, and propose adjustments to extant models to accommodate this finding.

Reward plays a crucial role in enhancing response inhibition. While it is generally assumed that the process of response inhibition involves attentional capture and the stopping of action, it is unclear whether this reflects a direct impact of reward on response inhibition or rather an indirect mediation via attentional capture. Here, we employed a revised stop-signal task (SST) that separated these two cognitive elements, by including a continue signal that required the same motor response as in go trials, but also attention to a cue, as in stop trials. We first confirmed the engagement of the right inferior frontal gyrus (IFG) during stop and continue trials, both of which required the attentional capture of the task-relevant cue, but only one of which required motor inhibition. The pre-supplementary motor area (pre-SMA) was specifically activated by the contrast of the stop trials with the continue trials. The results indicated that the IFG played an important role in attentional capture by unexpected stimuli, while the pre-SMA was responsible for the direct control of motor inhibition. Behavioral performance of the SST was improved by reward, and moreover, reward induced an increase in IFG activity. In addition, this advantageous reward effect was associated with enhanced connectivity between the anterior cingulate cortex and the IFG. These results indicated that the reward facilitation effect on response inhibition was indirect, occurring via a change in attentional processing. The present data confirm the specific function of the IFG and pre-SMA in response inhibition and provide straightforward evidence that reward can increase attentional capture-related activation in the IFG, which in turn improves the performance of response inhibition.

Excessive and dysregulated inflammation is known to contribute to disease progression. HSP90 is an intracellular chaperone known to regulate inflammatory processes including the NLRP3 inflammasome and secretion of the pro-inflammatory cytokine interleukin(IL)-1β. Here, primarily using an in vitro inflammasome ASC speck assay, and an in vivo model of murine peritonitis, we tested the utility of HSP90 inhibitors as anti-inflammatory molecules. We report that the HSP90 inhibitor EC144 effectively inhibited inflammatory processes including priming and activation of NLRP3 in vitro and in vivo. A specific inhibitor of the β HSP90 isoform was ineffective suggesting the importance of the α isoform in inflammatory signalling. EC144 inhibited IL-1β and IL-6 in vivo when administered orally, and was brain-penetrant. These data suggest that HSP90 inhibitors may be useful for targeting inflammation in diverse diseases that are worsened by the presence of inflammation.

Residual activations from previous task performance usually prime the system toward response repetition. However, when the task switches, the repetition of a response (RR) produces longer reaction times and higher error rates. Some researchers assumed that these RR costs reflect strategic inhibition of just executed responses and that this serves for preventing perseveration errors. We investigated whether the basic level of response inhibition is adapted to the overall risk of response perseveration. In a series of 3 experiments, we presented different proportions of stimuli that carry either a high or a low risk of perseveration. Additionally, the discriminability of high- and low-risk stimuli was varied. The results indicate that individuals apply several processing and control strategies, depending on the mixture of stimulus types. When discriminability was high, control was adapted on a trial-by trial basis, which presumably reduces mental effort (Experiment 1). When trial-based strategies were prevented, RR costs for low-risk stimuli varied with the overall proportion of high-risk stimuli (Experiments 2 and 3), indicating an adaptation of the basic level of response inhibition.

Dopaminergic drugs remain the mainstay of Parkinson's disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm.

Recent research suggests that response inhibition training can alter impulsive and compulsive behavior. When stop signals are introduced in a gambling task, people not only become more cautious when executing their choice responses, they also prefer lower bets when gambling. Here, we examined how stopping motor responses influences gambling. Experiment 1 showed that the reduced betting in stop-signal blocks was not caused by changes in information sampling styles or changes in arousal. In Experiments 2a and 2b, people preferred lower bets when they occasionally had to stop their response in a secondary decision-making task but not when they were instructed to respond as accurately as possible. Experiment 3 showed that merely introducing trials on which subjects could not gamble did not influence gambling preferences. Experiment 4 demonstrated that the effect of stopping on gambling generalized to different populations. Further, 2 combined analyses suggested that the effect of stopping on gambling preferences was reliable but small. Finally, Experiment 5 showed that the effect of stopping on gambling generalized to a different task. On the basis of our findings and earlier research, we propose that the presence of stop signals influences gambling by reducing approach behavior and altering the motivational value of the gambling outcome.

Is motor response inhibition supported by a specialised neuronal inhibitory control mechanism, or by a more general system of action updating? This pre-registered study employed a context-cueing paradigm requiring both inhibitory and non-inhibitory action updating in combination with functional magnetic resonance imaging to test the specificity of responses under different updating conditions, including the cancellation of actions. Cortical regions of activity were found to be common to multiple forms of action updating. However, functional specificity during response inhibition was observed in the anterior right inferior frontal gyrus. In addition, fronto-subcortical activity was explored using a novel contrast method. These exploratory results indicate that the specificity for response inhibition observed in right prefrontal cortex continued downstream and was observed in right hemisphere subcortical activity, while left hemisphere activity was associated with right-hand response execution. Overall, our findings reveal both common and distinct correlates of response inhibition in prefrontal cortex, with exploratory analyses supporting putative models of subcortical pathways and extending them through the demonstration of lateralisation.

Pleasurable stimuli, including reward, inhibit pain, but the level of the neuraxis at which they do so and the cerebral processes involved are unknown. Here, we characterized a brain circuitry mediating pain inhibition by reward. Twenty-four healthy participants underwent functional magnetic resonance imaging while playing a wheel of fortune game with simultaneous thermal pain stimuli and monetary wins or losses. As expected, winning decreased pain perception compared to losing. Inter-individual differences in pain modulation by monetary wins relative to losses correlated with activation in the medial orbitofrontal cortex (mOFC). When pain and reward occured simultaneously, mOFCs functional connectivity changed: the signal time course in the mOFC condition-dependent correlated negatively with the signal time courses in the rostral anterior insula, anterior-dorsal cingulate cortex and primary somatosensory cortex, which might signify moment-to-moment down-regulation of these regions by the mOFC. Monetary wins and losses did not change the magnitude of pain-related activation, including in regions that code perceived pain intensity when nociceptive input varies and/or receive direct nociceptive input. Pain inhibition by reward appears to involve brain regions not typically involved in nociceptive intensity coding but likely mediate changes in the significance and/or value of pain.

In order to treat dyspnea (=breathlessness) successfully, response inhibition (RI) as a major form of self-regulation is a premise. This is supported by research showing that self-regulation is associated with beneficial behavioral changes supporting treatment success in patients. Recent research showed that dyspnea has an impairing effect on RI, but the effects of repeated dyspnea exposure on RI remain unknown. Therefore, the present study tested the effects of repeated resistive load-induced dyspnea on RI over a 5-day period. Healthy volunteers (n = 34) performed the standard version of the Stroop task during baseline and dyspnea conditions on the first and fifth testing day and underwent an additional dyspnea exposure phase on each testing day. Variables of interest to investigate RI were reaction time, accuracy as well as the event-related potentials late positive complex (LPC) and N400 in the electroencephalogram. Reduced accuracy for incongruent compared to congruent stimuli during the dyspnea condition on the first testing day were found (p < 0.001). This was paralleled by a reduced LPC and an increased N400 for incongruent stimuli during the induction of dyspnea (p < 0.05). After undergoing dyspnea exposure, habituation of dyspnea intensity was evident. Importantly, on the fifth testing day, no differences between baseline, and dyspnea conditions were found for behavioral and electrophysiological measures of RI. These findings demonstrate that the impairing effect of dyspnea on RI disappeared after repeated dyspnea exposure in healthy participants. Translated to a clinical sample, it might cautiously be suggested that dyspnea exposure such as dyspnea perceived during physical exercise could reduce the impairing effect of dyspnea on RI which might have the potential to help increase self-regulation abilities and subsequent treatment efforts in dyspneic patients.

The combination of reward and potential threat is termed approach/avoidance conflict and elicits specific behaviors, including passive avoidance and behavioral inhibition (BI). Anxiety-relieving drugs reduce these behaviors, and a rich psychological literature has addressed how personality traits dominated by BI predispose for anxiety disorders. Yet, a formal understanding of the cognitive inference and planning processes underlying anxiety-like BI is lacking. Here, we present and empirically test such formalization in the terminology of reinforcement learning. We capitalize on a human computer game in which participants collect sequentially appearing monetary tokens while under threat of virtual "predation." First, we demonstrate that humans modulate BI according to experienced consequences. This suggests an instrumental implementation of BI generation rather than a Pavlovian mechanism that is agnostic about action outcomes. Second, an internal model that would make BI adaptive is expressed in an independent task that involves no threat. The existence of such internal model is a necessary condition to conclude that BI is under model-based control. These findings relate a plethora of human and nonhuman observations on BI to reinforcement learning theory, and crucially constrain the quest for its neural implementation. (PsycINFO Database Record