Tracing conflict-induced cognitive-control adjustments over time using aperiodic EEG activity.

Cognitive-control theories assume that the experience of response conflict can trigger control adjustments. However, while some approaches focus on adjustments that impact the selection of the present response (in trial N), other approaches focus on adjustments in the next upcoming trial (N + 1). We aimed to trace control adjustments over time by quantifying cortical noise by means of the fitting oscillations and one over f algorithm, a measure of aperiodic activity. As predicted, conflict trials increased the aperiodic exponent in a large sample of 171 healthy adults, thus indicating noise reduction. While this adjustment was visible in trial N already, it did not affect response selection before the next trial. This suggests that control adjustments do not affect ongoing response-selection processes but prepare the system for tighter control in the next trial. We interpret the findings in terms of a conflict-induced switch from metacontrol flexibility to metacontrol persistence, accompanied or even implemented by a reduction of cortical noise.

Auricular Transcutaneous Vagus Nerve Stimulation Specifically Enhances Working Memory Gate Closing Mechanism: A System Neurophysiological Study.

Everyday tasks and goal-directed behavior involve the maintenance and continuous updating of information in working memory (WM). WM gating reflects switches between these two core states. Neurobiological considerations suggest that the catecholaminergic and the GABAergic are likely involved in these dynamics. Both of these neurotransmitter systems likely underlie the effects to auricular transcutaneous vagus nerve stimulation (atVNS). We examine the effects of atVNS on WM gating dynamics and their underlying neurophysiological and neurobiological processes in a randomized crossover study design in healthy humans of both sexes. We show that atVNS specifically modulates WM gate closing and thus specifically modulates neural mechanisms enabling the maintenance of information in WM. WM gate opening processes were not affected. atVNS modulates WM gate closing processes through the modulation of EEG alpha band activity. This was the case for clusters of activity in the EEG signal referring to stimulus information, motor response information, and fractions of information carrying stimulus-response mapping rules during WM gate closing. EEG-beamforming shows that modulations of activity in fronto-polar, orbital, and inferior parietal regions are associated with these effects. The data suggest that these effects are not because of modulations of the catecholaminergic (noradrenaline) system as indicated by lack of modulatory effects in pupil diameter dynamics, in the inter-relation of EEG and pupil diameter dynamics and saliva markers of noradrenaline activity. Considering other findings, it appears that a central effect of atVNS during cognitive processing refers to the stabilization of information in neural circuits, putatively mediated via the GABAergic system.SIGNIFICANCE STATEMENT Goal-directed behavior depends on how well information in short-term memory can be flexibly updated but also on how well it can be shielded from distraction. These two functions were guarded by a working memory gate. We show how an increasingly popular brain stimulation techniques specifically enhances the ability to close the working memory gate to shield information from distraction. We show what physiological and anatomic aspects underlie these effects.

Turning the Light Switch on Binding: Prefrontal Activity for Binding and Retrieval in Action Control.

According to action control theories, responding to a stimulus leads to the binding of response and stimulus features into a common representation, that is, an event file. Repeating any component of an event file retrieves all previously bound information, leading to performance costs for partial repetitions measured in so-called binding effects. Although otherwise robust and stable, binding effects are typically completely absent in "localization tasks," in which participants localize targets with spatially compatible responses. Yet, it is possible to observe binding effects in such when location features have to be translated into response features. We hypothesized that this modulation of binding effects is reflected in task involvement of the dorsolateral pFC (DLPFC). Participants localized targets with either direct (i.e., spatially compatible key) or translated (i.e., diagonally opposite to the spatially compatible key) responses. We measured DLPFC activity with functional near-infrared spectroscopy. On the behavioral level, we observed binding effects in the translated response condition, but not in the direct response condition. Importantly, prefrontal activity was also higher in the translated mapping condition. In addition, we found some evidence for the strength of the difference in binding effects in behavioral data being correlated with the corresponding effects in prefrontal activity. This suggests that activity in the DLPFC reflects the amount of executive control needed for translating location features into responses. More generally, binding effects seem to emerge only when the task at hand involves DLPFC recruitment.

Inhibitory control in WM gate-opening: Insights from alpha desynchronization and norepinephrine activity under atDCS stimulation.

Our everyday activities require the maintenance and continuous updating of information in working memory (WM). To control this dynamic, WM gating mechanisms have been suggested to be in place, but the neurophysiological mechanisms behind these processes are far from being understood. This is especially the case when it comes to the role of oscillatory neural activity. In the current study we combined EEG recordings, and anodal transcranial direct current stimulation (atDCS) and pupil diameter recordings to triangulate neurophysiology, functional neuroanatomy and neurobiology. The results revealed that atDCS, compared to sham stimulation, affected the WM gate opening mechanism, but not the WM gate closing mechanism. The altered behavioral performance was associated with specific changes in alpha band activities (reflected by alpha desynchronization), indicating a role for inhibitory control during WM gate opening. Functionally, the left superior and inferior parietal cortices, were associated with these processes. The findings are the first to show a causal relevance of alpha desynchronization processes in WM gating processes. Notably, pupil diameter recordings as an indirect index of the norepinephrine (NE) system activity revealed that individuals with stronger inhibitory control (as indexed through alpha desynchronization) showed less pupil dilation, suggesting they needed less NE activity to support WM gate opening. However, when atDCS was applied, this connection disappeared. The study suggests a close link between inhibitory controlled WM gating in parietal cortices, alpha band dynamics and the NE system.

Neurophysiological processes reflecting the effects of the immediate past during the dynamic management of actions.

In recent years, there has been many efforts to establish a comprehensive theoretical framework explaining the working mechanisms involved in perception-action integration. This framework stresses the importance of the immediate past on mechanisms supporting perception-action integration. The present study investigates the neurophysiological principles of dynamic perception-action bindings, particularly considering the influence of the immediate history on action control mechanisms. For this purpose, we conducted an established stimulus-response binding paradigm during EEG recording. The SR-task measures stimulus-response binding in terms of accuracy and reaction time differences depending on the degree of feature overlap between conditions. Alpha, beta and theta band activity in distinct time domains as well as associated brain regions were investigated applying time-frequency analyses, a beamforming approach as well as correlation analyses. We demonstrate, for the first time, interdependencies of neuronal processes relying on the immediate past. The reconfiguration of an action seems to overwrite immediately preceding processes. The analyses revealed modulations of theta (TBA), alpha (ABA) and beta band activity (BBA) in connection with fronto-temporal structures supporting the theoretical assumptions of the considered conceptual framework. The close interplay of attentional modulation by gating irrelevant information (ABA) and binding and retrieval processes (TBA) is reflected by the correlation of ABA in all pre-probe-intervals with post-probe TBA. Likewise, the role of BBA in maintaining the event file until retrieval is corroborated by BBA preceding the TBA-associated retrieval of perception-action codes. Following action execution, TBA shifted towards visual association cortices probably reflecting preparation for upcoming information, while ABA and BBA continue to reflect processes of attentional control and information selection for goal-directed behavior. The present work provides the first empirical support for concepts about the neurophysiological mechanisms of dynamic management of perception and action.

EEG tensor decomposition delineates neurophysiological principles underlying conflict-modulated action restraint and action cancellation.

Executive functions are essential for adaptive behavior. One executive function is the so-called 'interference control' or conflict monitoring another one is inhibitory control (i.e., action restraint and action cancelation). Recent evidence suggests an interplay of these processes, which is conceptually relevant given that newer conceptual frameworks imply that nominally different action/response control processes are explainable by a small set of cognitive and neurophysiological processes. The existence of such overarching neural principles has as yet not directly been examined. In the current study, we therefore use EEG tensor decomposition methods, to look into possible common neurophysiological signatures underlying conflict-modulated action restraint and action cancelation as mechanism underlying response inhibition. We show how conflicts differentially modulate action restraint and action cancelation processes and delineate common and distinct neural processes underlying this interplay. Concerning the spatial information modulations are similar in terms of an importance of processes reflected by parieto-occipital electrodes, suggesting that attentional selection processes play a role. Especially theta and alpha activity seem to play important roles. The data also show that tensor decomposition is sensitive to the manner of task implementation, thereby suggesting that switch probability/transitional probabilities should be taken into consideration when choosing tensor decomposition as analysis method. The study provides a blueprint of how to use tensor decomposition methods to delineate common and distinct neural mechanisms underlying action control functions using EEG data.

Interactions of catecholamines and GABA+ in cognitive control: Insights from EEG and 1H-MRS.

Catecholamines and amino acid transmitter systems are known to interact, the exact links and their impact on cognitive control functions have however remained unclear. Using a multi-modal imaging approach combining EEG and proton-magnetic resonance spectroscopy (1H-MRS), we investigated the effect of different degrees of pharmacological catecholaminergic enhancement onto theta band activity (TBA) as a measure of interference control during response inhibition and execution. It was central to our study to evaluate the predictive impact of in-vivo baseline GABA+ concentrations in the striatum, the anterior cingulate cortex (ACC) and the supplemental motor area (SMA) of healthy adults under varying degrees of methylphenidate (MPH) stimulation. We provide evidence for a predictive interrelation of baseline GABA+ concentrations in cognitive control relevant brain areas onto task-induced TBA during response control stimulated with MPH. Baseline GABA+ concentrations in the ACC, the striatum, and the SMA had a differential impact on predicting interference control-related TBA in response execution trials. GABA+ concentrations in the ACC appeared to be specifically important for TBA modulations when the cognitive effort needed for interference control was high - that is when no prior task experience exists, or in the absence of catecholaminergic enhancement with MPH. The study highlights the predictive role of baseline GABA+ concentrations in key brain areas influencing cognitive control and responsiveness to catecholaminergic enhancement, particularly in high-effort scenarios.

Response stopping under conflict: The integrative role of representational dynamics associated with the insular cortex.

Coping with distracting inputs during goal-directed behavior is a common challenge, especially when stopping ongoing responses. The neural basis for this remains debated. Our study explores this using a conflict-modulation Stop Signal task, integrating group independent component analysis (group-ICA), multivariate pattern analysis (MVPA), and EEG source localization analysis. Consistent with previous findings, we show that stopping performance is better in congruent (nonconflicting) trials than in incongruent (conflicting) trials. Conflict effects in incongruent trials compromise stopping more due to the need for the reconfiguration of stimulus-response (S-R) mappings. These cognitive dynamics are reflected by four independent neural activity patterns (ICA), each coding representational content (MVPA). It is shown that each component was equally important in predicting behavioral outcomes. The data support an emerging idea that perception-action integration in action-stopping involves multiple independent neural activity patterns. One pattern relates to the precuneus (BA 7) and is involved in attention and early S-R processes. Of note, three other independent neural activity patterns were associated with the insular cortex (BA13) in distinct time windows. These patterns reflect a role in early attentional selection but also show the reiterated processing of representational content relevant for stopping in different S-R mapping contexts. Moreover, the insular cortex's role in automatic versus complex response selection in relation to stopping processes is shown. Overall, the insular cortex is depicted as a brain hub, crucial for response selection and cancellation across both straightforward (automatic) and complex (conditional) S-R mappings, providing a neural basis for general cognitive accounts on action control.

Neural representations of statistical and rule-based predictions in Gilles de la Tourette syndrome.

Gilles de la Tourette syndrome (GTS) is a disorder characterised by motor and vocal tics, which may represent habitual actions as a result of enhanced learning of associations between stimuli and responses (S-R). In this study, we investigated how adults with GTS and healthy controls (HC) learn two types of regularities in a sequence: statistics (non-adjacent probabilities) and rules (predefined order). Participants completed a visuomotor sequence learning task while EEG was recorded. To understand the neurophysiological underpinnings of these regularities in GTS, multivariate pattern analyses on the temporally decomposed EEG signal as well as sLORETA source localisation method were conducted. We found that people with GTS showed superior statistical learning but comparable rule-based learning compared to HC participants. Adults with GTS had different neural representations for both statistics and rules than HC adults; specifically, adults with GTS maintained the regularity representations longer and had more overlap between them than HCs. Moreover, over different time scales, distinct fronto-parietal structures contribute to statistical learning in the GTS and HC groups. We propose that hyper-learning in GTS is a consequence of the altered sensitivity to encode complex statistics, which might lead to habitual actions.

Extra Movements in Healthy People: Challenging the Definition and Diagnostic Practice of Tic Disorders.

The occurrence of motor/vocal tics, that is, "extra movements" and/or "extra vocalizations," is the leading diagnostic criterion for tic disorders. We show that extra movements are common also in healthy controls, so that a surplus of movements per se is not indicative of the presence of a tic disorder. This questions the usefulness of Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria for tic disorders in clinical practice. Apparently, it is not solely a surplus of movements that defines tic disorders. Instead, movement characteristics and patterns seem to play a crucial role. ANN NEUROL 2023;93:472-478.

Effects of Catecholaminergic and Transcranial Direct Current Stimulation on Response Inhibition.

BACKGROUND: The principle of gain control determines the efficiency of neuronal processing and can be enhanced with pharmacological or brain stimulation methods. It is a key factor for cognitive control, but the degree of how much gain control may be enhanced underlies a physical limit. METHODS: To investigate whether methylphenidate (MPH) and transcranial direct current stimulation (tDCS) share common underlying mechanisms and cognitive effects, we administered MPH and anodal tDCS (atDCS) over the right inferior frontal gyrus both separately and combined, while healthy adult participants (n = 104) performed a response selection and inhibition task. The recorded EEG data were analyzed with a focus on theta band activity, and source estimation analyses were conducted. RESULTS: The behavioral data show that MPH and atDCS revealed interactive effects on the ability to inhibit responses. Both MPH and atDCS modulated task-related theta oscillations in the supplementary motor area when applied separately, making a common underlying mechanism likely. When both stimulation methods were combined, there was no doubling of effects in the supplementary motor area but a shift to inferior frontal areas in the cortical network responsible for theta-driven processing. CONCLUSIONS: The results indicate that both MPH and atDCS likely share a common underlying neuronal mechanism, and interestingly, they demonstrate interactive effects when combined, which are most likely due to the physical limitations of gain control increases. The current study provides critical groundwork for future combined applications of MPH and non-invasive brain stimulation.

The Ability to Voluntarily Regulate Theta Band Activity Affects How Pharmacological Manipulation of the Catecholaminergic System Impacts Cognitive Control.

BACKGROUND: The catecholaminergic system influences response inhibition, but the magnitude of the impact of catecholaminergic manipulation is heterogeneous. Theoretical considerations suggest that the voluntary modulability of theta band activity can explain this variance. The study aimed to investigate to what extent interindividual differences in catecholaminergic effects on response inhibition depend on voluntary theta band activity modulation. METHODS: A total of 67 healthy adults were tested in a randomized, double-blind, cross-over study design. At each appointment, they received a single dose of methylphenidate or placebo and performed a Go/Nogo task with stimuli of varying complexity. Before the first appointment, the individual's ability to modulate theta band activity was measured. Recorded EEG data were analyzed using temporal decomposition and multivariate pattern analysis. RESULTS: Methylphenidate effects and voluntary modulability of theta band activity showed an interactive effect on the false alarm rates of the different Nogo conditions. The multivariate pattern analysis revealed that methylphenidate effects interacted with voluntary modulability of theta band activity at a stimulus processing level, whereas during response selection methylphenidate effects interacted with the complexity of the Nogo condition. CONCLUSIONS: The findings reveal that the individual's theta band modulability affects the responsiveness of an individual's catecholaminergic system to pharmacological modulation. Thus, the impact of pharmacological manipulation of the catecholaminergic system on cognitive control most likely depends on the existing ability to self-modulate relevant brain oscillatory patterns underlying the cognitive processes being targeted by pharmacological modulations.

Rethinking Movement Disorders.

At present, clinical practice and research in movement disorders (MDs) focus on the "normalization" of altered movements. In this review, rather than concentrating on problems and burdens people with MDs undoubtedly have, we highlight their hidden potentials. Starting with current definitions of Parkinson's disease (PD), dystonia, chorea, and tics, we outline that solely conceiving these phenomena as signs of dysfunction falls short of their complex nature comprising both problems and potentials. Such potentials can be traced and understood in light of well-established cognitive neuroscience frameworks, particularly ideomotor principles, and their influential modern derivatives. Using these frameworks, the wealth of data on altered perception-action integration in the different MDs can be explained and systematized using the mechanism-oriented concept of perception-action binding. According to this concept, MDs can be understood as phenomena requiring and fostering flexible modifications of perception-action associations. Consequently, although conceived as being caught in a (trough) state of deficits, given their high flexibility, people with MDs also have high potential to switch to (adaptive) peak activity that can be conceptualized as hidden potentials. Currently, clinical practice and research in MDs are concerned with deficits and thus the "deep and wide troughs," whereas "scattered narrow peaks" reflecting hidden potentials are neglected. To better delineate and utilize the latter to alleviate the burden of affected people, and destigmatize their conditions, we suggest some measures, including computational modeling combined with neurophysiological methods and tailored treatment. © 2024 International Parkinson and Movement Disorder Society.

Interindividual aperiodic resting-state EEG activity predicts cognitive-control styles.

The ability to find the right balance between more persistent and more flexible cognitive-control styles is known as "metacontrol." Recent findings suggest a relevance of aperiodic EEG activity and task conditions that are likely to elicit a specific metacontrol style. Here we investigated whether individual differences in aperiodic EEG activity obtained off-task (during resting state) predict individual cognitive-control styles under task conditions that pose different demands on metacontrol. We analyzed EEG resting-state data, task-EEG, and behavioral outcomes from a sample of N = 65 healthy participants performing a Go/Nogo task. We examined aperiodic activity as indicator of "neural noise" in the EEG power spectrum, and participants were assigned to a high-noise or low-noise group according to a median split of the exponents obtained for resting state. We found that off-task aperiodic exponents predicted different cognitive-control styles in Go and Nogo conditions: Overall, aperiodic exponents were higher (i.e., noise was lower) in the low-noise group, who however showed no difference between Go and Nogo trials, whereas the high-noise group exhibited significant noise reduction in the more persistence-heavy Nogo condition. This suggests that trait-like biases determine the default cognitive-control style, which however can be overwritten or compensated for under challenging task demands. We suggest that aperiodic activity in EEG signals represents valid indicators of highly dynamic arbitration between metacontrol styles, representing the brain's capability to reorganize itself and adapt its neural activity patterns to changing environmental conditions.

Neurophysiological principles of inhibitory control processes during cognitive flexibility.

Inhibitory control plays an indispensable role in cognitive flexibility. Nevertheless, the neurophysiological principles underlying this are incompletely understood. This owes to the fact that the representational dynamics, as coded in oscillatory neural activity of different frequency bands has not been considered until now-despite being of conceptual relevance. Moreover, it is unclear in how far distinct functional neuroanatomical regions are concomitantly involved in the processing of representational dynamics. We examine these questions using a combination of EEG methods. We show that theta-band activity plays an essential role for inhibitory control processes during cognitive flexibility across informational aspects coded in distinct fractions of the neurophysiological signal. It is shown that posterior parietal structures and the inferior parietal cortex seem to be the most important cortical region for inhibitory control processes during cognitive flexibility. Theta-band activity plays an essential role in processes of retrieving the previously inhibited representations related to the current task during cognitive flexibility. The representational content relevant for inhibitory processes during cognitive flexibility is coded in the theta frequency band. We outline how the observed neural mechanisms inform recent overarching cognitive frameworks on how flexible action control is accomplished.

A dissociable functional relevance of theta- and beta-band activities during complex sensorimotor integration.

Sensorimotor integration processes play a central role in daily life and require that different sources of sensory information become integrated: i.e. the information related to the object being under control of the agent (i.e. indicator) and the information about the goal of acting. Yet, how this is accomplished on a neurophysiological level is contentious. We focus on the role of theta- and beta-band activities and examine which neuroanatomical structures are involved. Healthy participants (n = 41) performed 3 consecutive pursuit-tracking EEG experiments in which the source of visual information available for tracking was varied (i.e. that of the indicator and the goal of acting). The initial specification of indicator dynamics is determined through beta-band activity in parietal cortices. When information about the goal was not accessible, but operating the indicator was required nevertheless, this incurred increased theta-band activity in the superior frontal cortex, signaling a higher need for control. Later, theta- and beta-band activities encode distinct information within the ventral processing stream: Theta-band activity is affected by the indicator information, while beta-band activity is affected by the information about the action goal. Complex sensorimotor integration is realized through a cascade of theta- and beta-band activities in a ventral-stream-parieto-frontal network.

Aperiodic neural activity reflects metacontrol.

Higher-level cognitive functions are mediated via complex oscillatory activity patterns and its analysis is dominating cognitive neuroscience research. However, besides oscillatory (period) activity, also aperiodic activity constitutes neural dynamics, but its relevance for higher-level cognitive functions is only beginning to be understood. The present study examined whether the broadband EEG aperiodic activity reflects principles of metacontrol. Metacontrol conceptualizes whether it is more useful to engage in more flexible processing of incoming information or to shield cognitive processes from incoming information (persistence-heavy processing). We examined EEG and behavioral data from a sample of n = 191 healthy participants performing a Simon Go/NoGo task that can be assumed to induce different metacontrol states (persistence-biased vs. flexibility-biased). Aperiodic activity was estimated using the FOOOF toolbox in the EEG power spectrum. There was a higher aperiodic exponent and offset in NoGo trials compared with Go trials, in incongruent (Go) trials compared with congruent (Go) trials. Thus, aperiodic activity increases during persistence-heavy processing, but decreases during flexibility-heavy processing. These findings link aperiodic features of the EEG signal and concepts describing the dynamics of how cognitive control modes are applied. Therefore, the study substantially extends the importance of aperiodic activity in understanding cognitive functions.

Modality-specific and modality-independent neural representations work in concert in predictive processes during sequence learning.

Probabilistic sequence learning supports the development of skills and enables predictive processing. It remains contentious whether visuomotor sequence learning is driven by the representation of the visual sequence (perceptual coding) or by the representation of the response sequence (motor coding). Neurotypical adults performed a visuomotor sequence learning task. Learning occurred incidentally as it was evidenced by faster responses to high-probability than to low-probability targets. To uncover the neurophysiology of the learning process, we conducted both univariate analyses and multivariate pattern analyses (MVPAs) on the temporally decomposed EEG signal. Univariate analyses showed that sequence learning modulated the amplitudes of the motor code of the decomposed signal but not in the perceptual and perceptual-motor signals. However, MVPA revealed that all 3 codes of the decomposed EEG contribute to the neurophysiological representation of the learnt probabilities. Source localization revealed the involvement of a wider network of frontal and parietal activations that were distinctive across coding levels. These findings suggest that perceptual and motor coding both contribute to the learning of sequential regularities rather than to a neither-nor distinction. Moreover, modality-specific encoding worked in concert with modality-independent representations, which suggests that probabilistic sequence learning is nonunitary and encompasses a set of encoding principles.

The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

It's not distance but similarity of distance: changing stimulus relations affect the control of action sequences.

Interacting with our environment happens on different levels of complexity: While there are individual and simple actions like an isolated button press, most actions are more complex and involve sequences of simpler actions. The degree to which multiple simple actions are represented as one action sequence can be measured via so-called response-response binding effects. When two or more responses are executed consecutively, they are integrated into one representation so that repetition of one response can start retrieval of the other. Executing such an action sequence typically involves responding to multiple objects or stimuli. Here, we investigated whether the spatial relation of these stimuli affects action sequence execution. To that end, we varied the distance between stimuli in a response-response binding task. Stimulus distance might affect response-response binding effects in one of two ways: It might directly affect the representation of the response sequence, making integration and retrieval between responses more likely if the responses relate to close stimuli. Alternatively, the similarity of stimulus distribution during integration and retrieval might be decisive, leading to larger binding effects if stimulus distance is identical during integration and retrieval. We found stronger binding effects with constant than with changing stimulus distance, indicating that action integration and retrieval can easily affect performance also if responses refer to separated objects. However, this effect on performance is diminished by changing spatial distribution of stimuli at the times of integration and retrieval.