Drug Cue Enhances Response Conflict and Reduces Conflict Adaptation in Methamphetamine Addiction

Drug Cue Enhances Response Conflict and Reduces Conflict Adaptation in Methamphetamine Addiction | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Drug Cue Enhances Response Conflict and Reduces Conflict Adaptation in Methamphetamine Addiction Yining Xu, Yingzhi Lu, Lihui Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8292739/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Mar, 2026 Read the published version in Psychological Research → Version 1 posted 9 You are reading this latest preprint version Abstract The stimulus-response learning account of cognitive control suggests that conflict between a task-relevant response and a task-irrelevant interfering response is contingent upon the stimulus-response associations, the strength of which can be reinforced by rewarding experience. Here, we employed a modified Simon task to investigate if patients with methamphetamine use disorder (MA) exhibited enhanced association between drug-related cues and task-irrelevant responses compared to healthy controls (HC). A lateral picture of a drug cue or a neutral cue was presented in either the left or right visual hemifield, which triggered an automatic response tendency at the spatially corresponding hand. Participants discriminated the color of the frame enclosing the cue, with responses either congruent or incongruent with the cue. Relative to the neutral cue, the drug cue induced a stronger response tendency at the spatially congruent hand in MA, and hence a larger interference when this response tendency was incongruent with the task-required hand (i.e., Simon effect). In contrast, the two cues induced comparable Simon effects in HC. Moreover, in MA, the Simon effect was smaller after an incongruent trial than after a congruent trial only for the neutral cue (i.e., conflict adaptation), but not for the drug cue. However, the conflict adaptation effects were equally observed for both cues in HC. These results suggest a MA-specific enhanced association between the drug cue and the task-irrelevant response. Our findings extend the theoretical scope of cognitive control into the clinical context, and provide new evidence in understanding the dysfunctional cognitive control in drug addiction. drug addiction response conflict conflict adaptation Simon effect Figures Figure 1 Figure 2 Figure 3 Introduction In daily life, we often respond to information from different sources in our environment. While the automatic responses learned through repeated stimulus-response associations bear the advantage of being fast and effortless, they can nevertheless be interfering and hence have to be overcome when they are in conflict with the response required by the task goal. For instance, getting used to the touchpad of one laptop facilitates the communication with that laptop, but the habitual touchpad responses would lead to mistakes when switching to a laptop with a different touchpad rule. Cognitive control needs to be recruited in such contexts to resolve the response conflict, suppressing the inappropriate automatic responses and implementing the goal-directed responses (see Badre, 2025 for a recent review). The efficient resolution of response conflict by cognitive control is a key feature of cognitive flexibility, and the dysfunction of cognitive control characterizes maladaptive behaviors such as addiction and obsessive-compulsive disorder (Chambers et al., 2009 ; Vandaele & Ahmed, 2021 ; Wang et al., 2024 ). Cognitive control is typically studied with tasks involving response conflict such as Go/NoGo, Stroop, Flanker and Simon tasks, where different responses are associated with different features of a presented stimulus. For instance, in the Stroop-like task (Stroop, 1935 ), a word is presented where the meaning and the ink color of the word refer to the same color (e.g., a word text ‘red’ in red) or different colors (e.g., a word text ‘red’ in green) while the task is to make discriminative responses to the ink color with different buttons. The behavioral response is interfered with when the meaning and the ink color of the word are incongruent with each other relative to when they are congruent, resulting in slowed response times (RTs) and/or increased error rates (Cohen et al., 1990 ; De Houwer, 2003 ). In a typical Simon task, a target is presented in either the left or right visual field, which induces an automatic response at the spatially corresponding hand (Simon, 1969 ; Hommel, 2011 ). The response hand required by the task goal (e.g., left hand for a red target and right hand for a blue target) is facilitated when its response code converges with the spatial code of the target (both left or both right), whereas it is slowed down when the two response codes are in conflict with each other (left target, right response hand or right target, left response hand), resulting in the Simon effect (Zhang & Kornblum, 1997 ; Proctor et al., 2011 ; Salzer et al., 2017 ). Cognitive control can be measured not only by different performances between congruent and incongruent conditions in conflict tasks (i.e., the conflict effect), but also by conflict adaptation, where the conflict effect after an incongruent trial is smaller than after a congruent trial (Gratton et al., 1992 ). While the phenomena of conflict effect and conflict adaptation have been widely observed, different accounts have been proposed to explain the mechanism (Botvinick et al., 2001 ; Hommel et al., 2004 ; Verguts & Notebaert, 2009 ; Chen et al., 2021 ; Egner, 2023 ). The conflict-monitoring account highlights the top-down control in the prefrontal cortex in overcoming the conflict (Botvinick et al., 2001 ; Blais et al., 2007 ). The competing response tendencies activated in an incongruent condition are detected by the anterior cingulate cortex, which up-regulates the lateral prefrontal cortex to overcome the inappropriate response activation and resolve the conflict. The level of cognitive control is higher following an incongruent trial than following a congruent trial, leading to stronger inhibition on the inappropriate response activation and hence reduced conflict effect. The account of stimulus-response learning highlights the associations between the stimulus and the response in triggering the conflict effect and the conflict adaptation (Hommel et al., 2004 ; Verguts & Notebaert, 2009 ; Bustamante et al., 2021 ). A typical conflict task involves two stimulus-response associations: the task-relevant association (e.g., the association between left hand and a red target in the Simon task) and the task-irrelevant association (e.g., the association between right hand and a target on the right). The task-irrelevant association is enhanced after a congruent trial, which facilitates the response to the following congruent trial whereas delays the response to the following incongruent trial. By contrast, the task-irrelevant association is weakened after an incongruent trial, which facilitates the response to the following incongruent trial whereas delays the response to the following congruent trial. A growing body of evidence has shown that cognitive control can be modulated by reward, a crucial reinforcer and motivator of human behavior (Pessoa, 2009 ; Krebs et al., 2010 ; Braem et al., 2012 ; Botvinick & Braver, 2015 ; Kang et al., 2017 ; Wang et al., 2019 ). On the one hand, it has been shown that the conflict effects in various tasks were reduced during the expectation of reward (Boehler et al., 2014 ; Soutschek et al., 2015 ; Kang et al., 2017 ; 2018 ). In line with the conflict-monitoring account, it has been suggested that reward enhances the top-down control in the prefrontal cortex, which prioritizes the task-relevant processing while inhibiting the task-irrelevant processing (Padmala & Pessoa, 2011 ; Botvinick & Braver, 2015 ). On the other hand, however, it has been shown that the conflict effect was enlarged when the target was associated with reward (Freeman et al., 2014 ; Wang et al., 2019 ; 2021 ). For instance, in a Simon task, Wang et al. ( 2019 ) presented a target letter in the left or right visual field, and the task was to make discriminative responses to the identity of the lateral target with the left or right hand. Importantly, the target letter in each trial could either lead to a receipt of high monetary reward upon a quick and correct response, or a low monetary reward. Results showed that the spatial congruency effect was larger when the target was associated with high reward than when the target was associated with low reward (Wang et al., 2019 ; 2021 ). This reward-enlarged conflict effect cannot be incorporated into the top-down control account, which would have predicted an otherwise reduced conflict by reward. Instead, the reward-enlarged conflict effect is consistent with the account of stimulus-response learning, as the task-irrelevant association (the automatic response to the location of the target) can be reinforced by reward. Beyond the reward-enlarged conflict effect, the stimulus-response learning account can also be applied to explaining the maladaptive behaviors of self-control disorders such as drug addiction. According to the neuropsychological model of drug addiction, the habitual drug seeking and use have been strengthened by the drug-induced rewarding effect and sensitization (i.e., increasing doses and more frequent use of drugs to reach the same drug effect over the course of addiction), resulting in impaired cognitive control (Robinson & Berridge, 1993 ; Everitt & Robbins, 2016 ; Vandaele & Ahmed, 2021 ). Although the dysfunction of cognitive control in drug addiction has been well documented as overall poorer performance in conflict tasks relative to healthy controls (HC) (Smith et al., 2013 ; Wang et al., 2018 ; Zilverstand et al., 2018 ), it remains unclear if drug use leads to enhanced task-irrelevant association between the drug cue and the behavioral response. Here, we adopted the Simon task to test this hypothesis in populations with methamphetamine (MA) use disorder. Following the design of the previous studies (Wang et al., 2019 ; 2021 ), a picture of a drug cue or a neutral cue was presented on the left or right visual hemifield to induce the automatic response tendency at the spatially corresponding hand (Fig. 1 ). The task was to discriminate the color of the frame in which the picture was embedded, with the response hand either on the same side or the opposite side of the target location, rendering spatial congruency between the automatic task-irrelevant response tendency and the task-relevant response. We thus predicted that, relative to the neutral cue, the drug cue would trigger a stronger response tendency at the spatially corresponding hand and lead to a larger Simon effect between the congruent and incongruent conditions. Crucially, this enhanced response tendency and enlarged Simon effect would only be observed in participants with drug addiction, but not in the HC group. Moreover, we also investigated if and how the conflict adaptation of the Simon effect was dependent on the cue. We predicted that the Simon effect would be smaller following an incongruent trial than following a congruent trial in the HC group, regardless of whether there was a drug cue or neutral cue, i.e., a typical conflict adaptation effect. In the MA group, however, the conflict adaptation would be smaller (Li et al., 2022 ) or might even disappear for the drug cue relative to the neutral cue, as the long-term association between the drug cue and the response could override the transiently changed association from the previous trial. Methods Participants Sample size was estimated with G*Power 3.0 (Faul et al., 2007 ) according to a previous study employing the reward-based Simon paradigm (Wang et al., 2019 ). Specifically, a significant interaction between reward level and spatial congruency was observed in the previous study with an alpha = 0.022 and an effect size of η 2 p = 0.248. Given the statistics in the previous study, a correlation among repeated measures = 0.5 and a default setting of nonsphericity correction (ε = 1), a sample size of 20 was required to achieve an expected power of 99%. Following this criterion while considering potential data exclusion, 22 patients (all males, Table 1 ) with MA use disorder were included to complete the experiment. Patients were recruited from a male drug rehabilitation center, with the following inclusion criteria: 1) met the DSM-5 criteria for methamphetamine use disorder; 2) age 18 years or older; 3) normal vision and normal color vision; 4) right-handed. Patients were excluded if they had a history of neurological illness or had been diagnosed with any psychiatric disorder meeting the DSM-5 criteria other than nicotine use disorder. Twenty-two healthy controls (HCs) were recruited from the general population. They were first screened to match the education level of the patients, and were then included with the following inclusion criteria: 1) males, with age 18 years or older; 2) no current diagnosis or history of any psychiatric disorder meeting the DSM-5 criteria; 3) normal vision and normal color vision; 4) right-handed. None of them had a family history of psychiatric disorder. All patients and HCs reported no acute physical disease or chronic neurological disease. Written informed consent was obtained from each participant before the experiment. The study was conducted in accordance with the principles of the Declaration of Helsinki, and was approved by the Ethics Committee of Shanghai University of Sport (No. 102772019RT044). Table 1 Demographic characteristics of the two groups of participants (MA: methamphetamine use disorder, HC: healthy controls). MA HC statistics p Age (SD) 41.23 (8.67) 41.74 (10.09) t (21) = 0.19 0.848 Years of education (SD) 8.32 (2.92) 8.32 (2.92) t 0.999 Total years of smoking (SD) 20.04 (10.57) 8.63 (9.09) t (21) = 3.84 < 0.001 Total years of alcohol drinking (SD) 16.55 (12.06) 8.14 (8.90) t (21) = 2.63 0.012 Total years of substance use (SD) 10.91 (6.70) / Abstinent duration in months (SD) 19.82 (9.38) / Stimuli and Experimental Design Stimuli were 24 pictures of MA-related scenes (drug cue) and 24 pictures of daily-life decorative accessories unrelated to any drug (neutral cue). Stimuli were presented against a black background on a laptop screen (34.5 * 19.5 cm). A white cross (0.5° * 0.5° of visual angle) was presented at the center of the screen as the central fixation. In each trial, a picture of either a drug cue or a neutral cue (2.4° * 2.4° of visual angle) embedded in a red or blue frame (2.6° * 2.6° of visual angle) was presented to the left or right of the central fixation (4.5° distance). The color of the frame was orthogonal to the cue type of the presented picture. Participants were required to discriminate the color of the frame (red vs. blue) by pressing the “z” or “m” button on the keyboard using their left or right index finger, respectively. Thus, the location of the presented picture was either congruent (the picture on the right embedded in a blue frame or the picture on the left embedded in a red frame) or incongruent (the picture on the right embedded in a red frame or the picture on the left embedded in a blue frame) with the required responding hand. Therefore, the experiment had a 2 (Group: MA vs. HC) * 2 (Cue Type: drug cue vs. neutral cue) * 2 (Spatial Congruency: congruent vs. incongruent) design. Participants were informed to pay attention to the color of the picture frame and respond as quickly and accurately as possible. Procedure Participants were tested individually in a sound-attenuated environment. Each participant was seated in front of a laptop screen, and was required to fixate on the central fixation throughout each trial. The eye-to-screen distance was approximately 60 cm. Each trial started with the presentation of the central fixation for a varying duration of 400/500/600/700 ms. The picture was then presented for 600 ms, followed by a blank screen which lasted up to 1900 ms until a response was given. Responses made after this time window were identified as omissions. The inter-trial interval was a blank screen of 1000 ms. There were 24 trials in each of the 4 experimental conditions. The 96 trials in total were mixed and divided into 4 blocks of equal length (24 trials). Trials from the 4 conditions were presented in a random order in each block. There was a break between each two blocks, the length of which was self-paced. To get participants familiar with the task, a short practice session of 8 trials was provided prior to the formal experiment. The pictures presented in the practice session were all neutral cues that were not presented in the formal experiment. The practice session was repeated if the response accuracy was below 75%. Statistical analysis of data For each participant, omissions and trials with incorrect responses in each condition were excluded from data analysis. Mean reaction time (RT) of the remaining trials was then calculated for each condition. The error rate (ER) in each condition was calculated as the proportion of omissions and incorrect trials against the total trials in that condition. A 2 (Group: MA vs. HC) * 2 (Cue Type: drug cue vs. neutral cue) * 2 (Spatial Congruency: congruent vs. incongruent) repeated-measures ANOVA was conducted on the mean RT and the ER respectively, with Group as a between-subjects factor and Cue Type and Spatial Congruency as within-subject factors. The alpha level for rejecting a null hypothesis was set to 0.05. Paired t -tests were further conducted following a significant interaction. To investigate how the conflict adaptation was affected by the drug cue, trials in each condition were further sorted according to the congruency of the previous trial. The Simon effect, in terms of RT and ER difference between the incongruent condition and the congruent condition, was calculated for each of the four conditions: drug cue following a congruent trial, drug cue following an incongruent trial, neutral cue following a congruent trial, neutral cue following an incongruent trial (Table 3 ). A 2 (Previous Congruency: congruent vs. incongruent) * 2 (Cue Type: drug vs. neutral) ANOVA was then conducted on the Simon effect for the MA group and the HC group, respectively. Table 2 Mean and standard errors (in parentheses) of reaction time (RT, ms) and error rate (ER, %) in each experimental condition and group (MA: methamphetamine use disorder, HC: healthy controls). Measurement Group Drug Cue Neutral Cue Congruent Incongruent Congruent Incongruent RT MA 552 (12) 608 (18) 583 (18) 605 (15) HC 551 (23) 591 (24) 559 (19) 609 (21) ER MA 2.5 (1.0) 6.6 (1.3) 5.3 (1.4) 7.4 (1.3) HC 8.5 (2.3) 9.3 (1.8) 8.7 (2.0) 13.1 (2.6) Results The Simon effect Table 2 summarizes the mean RT and error rate in each condition of each group. The 2 (Group: MA vs. HC) * 2 (Cue Type: drug vs. neutral) * 2 (Congruency: congruent vs. incongruent) repeated-measures ANOVA on RTs showed a main effect of Cue Type, F (1, 42) = 8.46, p = 0.006, η 2 p = 0.168, indicating overall faster responses to the drug cue than to the neutral cue, a main effect of Congruency, F (1, 42) = 78.56, p < 0.001, η 2 p = 0.652, indicating overall faster responses to the spatially congruent cue than to the incongruent cue, i.e., a typical Simon effect. However, the main effect of Group did not reach significance, F < 1, indicating comparable RTs between the two groups. Importantly, there was a three-way interaction between Group, Cue Type, and Congruency, F (1, 42) = 8.49, p = 0.006, η 2 p = 0.168, whereas the two-way interactions did not reach significance, all p > 0.1. Given the three-way interaction, a 2 (Cue Type: drug vs. neutral) * 2 (Congruency: congruent vs. incongruent) repeated-measures ANOVA was conducted for MA and HC respectively. For MA, both the main effect of Cue Type, F (1, 21) = 6.32, p = 0.020, η 2 p = 0.231, and the main effect of Congruency, F (1, 21) = 34.91, p < 0.001, η 2 p = 0.624, were significant (Fig. 2 , left). Moreover, the interaction between Cue Type and Congruency was also significant, F (1, 21) = 7.84, p = 0.011, η 2 p = 0.272. This interaction was due to a larger Simon effect induced by the drug cue (RT difference between congruent and incongruent conditions: 56 ms) than by the neutral cue (RT difference: 22 ms), Cohen’s d = 0.597, 95%CI [8.84, 59.90]. Further t -tests teasing apart the interaction showed that the drug cue induced faster responses than the neutral cue in the congruent condition (RT difference: 31 ms), t (21) = 3.18, p = 0.005, Cohen’s d = 0.867, 95%CI [10.60, 50.86], whereas the responses to the two types of cues were comparable in the incongruent condition, t < 1. The faster responses to the drug cue than the neutral cue in the congruent condition also manifested at the individual level, as 17 out of 22 MA participants showed this pattern, whereas there was no such clear pattern in the incongruent condition, with 10 out of 22 MA participants responding faster to the drug cue than the neutral cue (Fig. 2 , left). For HC (Fig. 2 , right), the main effect of Cue Type was not significant, F (1, 21) = 3.05, p = 0.095, η 2 p = 0.127; the main effect of Congruency was significant, F (1, 21) = 43.76, p < 0.001, η 2 p = 0.676. However, the interaction between Cue Type and Congruency did not reach significance, F (1, 21) = 1.16, p = 0.293. The three-way ANOVA on the ER showed a main effect of Cue Type, F (1, 42) = 4.20, p = 0.042, η 2 p = 0.091, indicating overall lower error rates to drug cue than neutral cue, a main effect of Congruency, F (1, 42) = 9.30, p = 0.004, η 2 p = 0.181, indicating overall lower ER to spatially congruent cue than incongruent cue, and a main effect of Group, F (1, 42) = 5.00, p = 0.031, η 2 p = 0.106, indicating lower ER in the MA group than in the control group. However, none of the two-way interactions reached significance, all F < 1. The three-way interaction did not reach significance either, F (1, 42) = 3.00, p = 0.090. Therefore, the results of ER did not show the opposite pattern to the results of RT, ruling out that the observed effects based on RT was due to potential speed-accuracy trade-off. Table 3 Mean and standard errors (in parentheses) of Simon effect, in terms of RT difference (ms) and ER difference (%) in each condition and group (MA: methamphetamine use disorder, HC: healthy control). Measurement Group Drug Cue Neutral Cue Previous Congruent Previous Incongruent Previous Congruent Previous Incongruent RT MA 59 (9) 49 (12) 37 (10) -7 (11) HC 74 (15) 6 (14) 77 (20) 33 (13) ER MA 6.4 (1.9) 1.9 (1.9) 5.3 (2.3) -1.3 (2.1) HC 4.7 (2.8) -2.9 (3.1) 4.1 (2.5) 4.2 (2.3) The conflict adaptation of the Simon effect Table 3 summarizes the size of the Simon effect in each condition. For the MA group, the main effect of Previous Congruency was significant, F (1, 21) = 7.92, p = 0.010, η 2 p = 0.274, indicating a larger Simon effect following a congruent trial than following an incongruent trial, i.e., a typical conflict adaptation. The main effect of Cue Type was significant, F (1, 21) = 10.89, p = 0.010, η 2 p = 0.341, indicating a larger Simon effect for a drug cue than for a neutral cue (Fig. 3 , left). Importantly, the interaction between Previous Congruency and Cue Type was also significant, F (1, 21) = 6.29, p = 0.020, η 2 p = 0.231. Further t -tests teasing apart the interaction showed that the conflict adaptation was observed only for the neutral cue (Simon effect: 37 ms following a congruent trial vs. -7 ms following an incongruent trial), t (21) = 3.95, p < 0.001, Cohen’s d = 0.842, 95%CI [20.72, 66.80]. For the drug cue, however, the Simon effect following a congruent trial (59 ms) was statistically equivalent to the Simon effect following an incongruent trial (49 ms), t < 1. This null effect was further verified by the Bayes factor analysis (Wagenmakers, Marsmann et al., 2018 ), showing that the null hypothesis “the Simon effect following a congruent trial did not differ from the Simon effect following an incongruent trial” was 3.33 times (> 3 as moderate evidence, Wagenmakers, Love et al., 2018 ) more likely to be true than the alternative hypothesis that “the Simon effect following a congruent trial was different from the Simon effect following an incongruent trial”. For the HC group, the two-way ANOVA revealed only a significant main effect of Previous Congruency, F (1, 21) = 16.71, p < 0.001, η 2 p = 0.443, whereas neither the main effect of Cue Type, F (1, 21) = 1.04, p = 0.320, nor the interaction, F < 1, reached significance, indicating comparable conflict adaptation effects for the drug cue and the neutral cue (Fig. 3 , right). Similar analyses were performed on the Simon effect based on ER. For MA, the two-way ANOVA showed only a significant main effect of Previous Congruency, F (1, 21) = 10.89, p = 0.003, η 2 p = 0.342, indicating a larger Simon effect following a congruent trial than following an incongruent trial, i.e., a typical conflict adaptation. However, neither the main effect of Cue Type, F (1, 21) = 1.02, p = 0.324, nor the interaction, F < 1, reached significance. For HC, the results showed the same pattern: the main effect of Previous Congruency was marginally significant, F (1, 21) = 3.78, p = 0.066, η 2 p = 0.152, whereas neither the main effect of Cue Type, F (1, 21) = 1.58, p = 0.222, nor the interaction, F (1, 21) = 1.91, p = 0.182, reached significance. Discussion In the present study, we adopted a modified Simon task to investigate if there was an enhanced task-irrelevant association between the drug cue and the automatic response at the spatially congruent hand in individuals with drug addiction. We tested this hypothesis both by comparing the Simon effects induced by the drug cue versus neutral cue, and by examining the adaptation effects of the Simon conflict in the presence of the drug cue versus neutral cue. The results showed that the MA group exhibited a significantly larger Simon effect for the drug cue compared to the neutral cue, whereas the Simon effects in the HC group were equivalent between the drug-cue condition and the neutral-cue condition. Further tests showed that the enlarged Simon effect was due to significantly facilitated responses by the drug cue than the neutral cue in the congruent condition. Moreover, the adaptation effects of the Simon conflict in the HC group were equally observed for both the drug cue and the neutral cue, with a smaller Simon effect following an incongruent trial than following a congruent trial. In the MA group, however, such adaptation effect occurred only for the neutral cue but not for the drug cue. When responding to the drug cue, the Simon effects were comparable regardless of whether the previous trial was congruent or incongruent. The convergent evidence consistently confirmed the enhanced association between the automatic response tendency and the task-irrelevant location of the drug cue, resulting in the overall enlarged Simon effect and reduced conflict adaptation. The present observations are consistent with existing findings showing that the response conflict can be enlarged by reward (Krebs et al., 2010 ; Freeman et al., 2014 ; Wang et al., 2019 ; Wang et al., 2021 ). For instance, in a Stroop task where discriminative responses were required among 4 alternative colors of the presented word, correct and fast responses to two colors were associated with (reward-related colors) whereas responses to the other two colors were not associated with reward (reward-unrelated colors) (Krebs et al., 2010 ). While the performance was generally enhanced in responding to reward-related colors relative to reward-unrelated colors, the word meaning referring to the reward-related color led to stronger interference and hence larger Stroop conflict than the word meaning referring to the reward-unrelated color. These results suggested that the association between a task-relevant feature (i.e., color) and the corresponding response transferred to the task-irrelevant feature (i.e., word meaning). Similarly in a Simon task where correct and fast responses to the target letter were associated with high- or low-reward, the automatic response to the location of the high-reward target was facilitated more than the low-reward target, resulting in a reward-enlarged Simon effect (Wang et al., 2019 ; 2021 ). In an extension of these findings, the current results provide evidence from clinical populations that people with drug addiction, who had long-term experience associating drug cues with the rewarding effects of drug use, exhibited a stronger response tendency to the task-irrelevant feature of the drug cue relative to the neutral cue. Evidence also comes from the reward-modulated conflict adaptation effect (Braem et al., 2012 ; Sturmer et al., 2011). For instance, in a Simon task where only the responses with the first percentile of speed were associated with monetary gain, the adaptation effect of the Simon conflict was larger following a reward trial than a no-reward trial (Sturmer et al., 2011). The enhanced conflict adaptation after a reward trial than after a no-reward trial was also observed in a flanker task, suggesting that reward strengthened the stimulus-response association (Braem et al., 2012 ). One may note that the reward-enlarged conflict adaptation effects in these studies appear to be in contrast to the reduced conflict adaptation by the drug cue in the present study. However, it should be noted that, in these previous studies, reward was not associated with any particular stimulus but with the response in a particular trial, rendering a transiently enhanced task-relevant association. Relative to a congruent trial, the reward-enhanced association between the stimulus and response in an incongruent trial thus facilitated the response in the next trial when it was also incongruent (i.e., unchanged stimulus-response mapping) whereas delayed the response when it was congruent (i.e., changed stimulus-response mapping). By contrast, in the present study, we focused on how the adaptation effect was affected by the reward significance of the stimulus in the current trial but not the reward significance of the response in the previous trial. The long-term drug use resulted in a sustained stronger stimulus-response association specific to the drug cue but not the neutral cue in the MA group, which in turn was immune to the transient change of the association from the previous trial and led to comparable Simon effects. Along with the collective evidence of the reward-modulated response conflict and the conflict adaptation in the above-mentioned studies, the enlarged Simon effect and reduced conflict adaptation by the drug cue in the present study cannot be simply accounted for by the top-down control mechanism. Specifically, it has been suggested that reward can enhance the top-down control in the prefrontal cortex, which prioritizes the task-relevant processing while inhibiting the task-irrelevant processing (Padmala & Pessoa, 2011 ; Botvinick & Braver, 2015 ). From this perspective, the response conflict would have been lower and the adaptation effect would have been larger at the presence of a reward-predictive stimulus. These findings thus support the account of the stimulus-response learning (Hommel et al., 2004 ; Verguts & Notebaert, 2009 ; Chen et al., 2021 ) in the way that the strengthened association between a response to a reward-predictive stimulus can transfer to the other features of this stimulus and enhance the task-irrelevant response tendencies. Although our findings clearly suggest a role of the stimulus-response learning in the response conflict and conflict adaptation, it does not mean that the top-down control mechanism was not present at all. In the previous study of the reward-enhanced Simon effect, the functional connectivity between the pre-supplementary area and the right inferior frontal cortex was more strongly recruited to cope with the reward-enhanced response conflict (Wang et al., 2019 ). Taken together, these results suggest that cognitive control acts as a coordinated system of stimulus-response learning and top-down control (Bustamante et al., 2021 ; Ritz et al., 2022 ). Our findings agree with recent studies using other approaches to manipulate the stimulus-response associations (Chen et al., 2021 ; Zhang et al., 2022 ; Held et al., 2024 ; Li et al., 2025 ). For instance, in a Simon task, reward was presented only after correct and fast responses to congruent trials for one group of participants (RC group), was presented only after correct and fast responses to in congruent trials for another group of participants (RI group), and was equally presented after correct and fast responses to both types of trials for a third group of participants (neutral group) (Chen et al., 2021 ). Results showed that, relative to the neutral group, the Simon effect was increased in the RC group and was even reversed in the RI group, with faster responses in the incongruent trials than in the congruent trials. These results suggested that reward enhanced the congruent stimulus-response associations in the RC group and enhanced the incongruent stimulus-response associations in the RI group, which added to and overridden the original, reward-neutral stimulus-response associations, respectively (Chen et al., 2021 ). Notably, in the initial learning stage (e.g., the first two blocks) of the same study, the learning effects were more prominent in the RC condition than the RI condition (Chen et al., 2021 ). In another study where a Stroop task was adopted, selectively presenting reward after responses to incongruent trials only led to a weak reduction of the conflict effect, whereas selectively presenting reward after responses to congruent trials led to a strong increase of the conflict effect (Prevel et al., 2021 ). Collectively, these results suggested a biased learning effect for the automatic stimulus-response associations, which also helps to explain why the enlarged Simon effect was dominated by the fast response to the drug cue in the congruent condition. Our findings also provide new insights into the dysfunctional cognitive control in drug addiction. In a traditional view, the deficits are understood as a dysfunction of the top-down inhibitory control governed by the fronto-striatal pathway in the brain, where the dopamine-mediated regulation has been disrupted by drug use, resulting in overall lowered performance in conflict tasks (Smith et al., 2013 ; Wang et al., 2018 ; Zilverstand et al., 2018 ). However, the observed effects here cannot be simply due to an impaired function of top-down inhibitory control, as the MA group did not show overall lowered task performance relative to the HC group. Specifically, the overall RTs were comparable between the two groups, and the overall ER was even lower in the MA group than the HC group in both the congruent and incongruent conditions. In addition, the conflict adaptation was still observed for the neutral cue in MA, suggesting that the observed effects were specific to the drug cue rather than an overall changed ability of cognitive control. The observed effects thus occur mainly at the cost of the dominant automatic response tendency to the drug-related stimuli. One limitation of the present study is that only male participants were included in both the MA group and hence the matched HC group. Although to our knowledge there is no fundamental sex difference in either the general Simon effect or the reward-modulated Simon effect (Wang et al., 2019 , 2021 ), the generalization of the present findings to female participants still needs to be verified. Conclusion In summary, the present study showed that, relative to a neutral cue, a drug cue induced an enlarged spatial response conflict (i.e., Simon effect) in MAs, whereas the conflict effects were comparable for the drug cue and the neutral cue in HCs. Moreover, while both cues induced comparable adaptation effects of the response conflict in HCs, the drug cue reduced the adaptation effect relative to the neutral cue in MAs. The results suggest enhanced task-irrelevant drug cue-response association in MAs and shed light on the mechanism of impaired cognitive control in drug addiction. Declarations Acknowledgements We thank Dr. Zhongbin Su for the data illustrations. This study was supported by the National Natural Science Foundation of China (No. 32000779) and the Fundamental Research Funds for Central Universities (No. YG2025QNB13) to LW. Author contribution s L.W. conceived and designed the study, Y.X. collected and analyzed the data, L.W. and Y.L. supervised the project, L.W. and Y.X. wrote the original draft, L.W., Y.X. and Y.L. revised and approved the final manuscript. Conflict of interest The authors declare no conflict of interest. Data Availability Data of the present study has been deposited at OSF, accession code: osf.io/5c4bk/. References Badre, D. (2025). Cognitive control. Annual Review of Psychology , 76 , 167–195. Blais, C., Robidoux, S., Risko, E. F., & Besner, D. (2007). 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Reward facilitates response conflict resolution via global motor inhibition: electromyography evidence. Psychophysiology , 58 (10), e13896. Wang, W., Worhunsky, P. D., Zhang, S., Thang, M. E., Potenza, M. N., & Li, C. (2018). Response inhibition and fronto-striatal-thalamic circuit dysfunction in cocaine addiction. Drug and Alcohol Dependence , 192 , 137–145. Wang, Z., Zhang, C., Guo, Q., Fan, Q., & Wang, L. (2024). Concurrent oculomotor hyperactivity and deficient anti-saccade performance in obsessive-compulsive disorder. Journal of Psychiatric Research , 180 , 402–410. Vandaele, Y., & Ahmed, S. H. (2021). Habit, choice, and addiction. Neuropsychopharmacology : Official Publication Of The American College Of Neuropsychopharmacology , 46 (4), 689–698. Verguts, T., & Notebaert, W. (2009). Adaptation by binding: A learning account of cognitive control. Trends in Cognitive Sciences , 13 , 252–257. Zhang, D., Liu, L., Huang, B., & Wang, L. (2022). Neural dynamics underlying cognitive control modulated by reinforcement learning of irrelevant stimulus-response associations. Journal of Cognitive Neuroscience , 34 (11), 2048–2064. Zhang, J., & Kornblum, S. (1997). Distributional analysis and De Jong, Liang, and Lauber’s (1994) dual-process model of the Simon effect. Journal of Experimental Psychology: Human Perception & Performance , 23 (5), 1543–1551. Zilverstand, A., Huang, A. S., Alia-Klein, N., & Goldstein, R. Z. (2018). Neuroimaging Impaired Response Inhibition and Salience Attribution in Human Drug Addiction: A Systematic Review. Neuron , 98 (5), 886–903. https://doi.org/10.1016/j.neuron.2018.03.048 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 12 Mar, 2026 Read the published version in Psychological Research → Version 1 posted Editorial decision: Revision requested 29 Jan, 2026 Reviews received at journal 22 Jan, 2026 Reviews received at journal 07 Jan, 2026 Reviewers agreed at journal 11 Dec, 2025 Reviewers agreed at journal 11 Dec, 2025 Reviewers invited by journal 11 Dec, 2025 Editor assigned by journal 09 Dec, 2025 Submission checks completed at journal 08 Dec, 2025 First submitted to journal 06 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8292739","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":560196769,"identity":"1b8d61a6-0a9b-4a78-b288-7cacdb4ea8c2","order_by":0,"name":"Yining Xu","email":"","orcid":"","institution":"National Center for Mental Disorders, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yining","middleName":"","lastName":"Xu","suffix":""},{"id":560196770,"identity":"96d2e689-d787-40ed-82b2-1d057e51e0a9","order_by":1,"name":"Yingzhi Lu","email":"","orcid":"","institution":"Shanghai 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1","display":"","copyAsset":false,"role":"figure","size":410342,"visible":true,"origin":"","legend":"\u003cp\u003e(A) An example picture of drug cue and neutral cue. (B) The picture was either presented left or right to the central fixation. Participants discriminated the color of the frame that the picture was embedded in, left index finger for red and right index finger for blue. This design renders the location of picture congruent or incongruent with the response hand. (C) Stimuli sequence in an example trial (neutral cue, incongruent).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8292739/v1/7567c7037fe82c668be5b48e.png"},{"id":98438414,"identity":"1c24154d-8f52-4462-b8d6-b5ba1acf4dd1","added_by":"auto","created_at":"2025-12-17 16:59:13","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":514634,"visible":true,"origin":"","legend":"\u003cp\u003eIndividual (line) and mean (diamond) reaction times (RT) are shown as a function of cue type (drug cue vs. neutral cue) and spatial congruency (congruent vs. incongruent) for the methamphetamine group (MA, left) and the healthy control group (HC, right). ***\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001, *\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8292739/v1/d2c819af7fe358b6f70d401f.png"},{"id":98438368,"identity":"b103c3b4-b9da-4c5c-a476-a630d8d7b08f","added_by":"auto","created_at":"2025-12-17 16:59:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":450005,"visible":true,"origin":"","legend":"\u003cp\u003eThe Simon effect (RT difference between incongruent and congruent trials) was calculated for each individual (line) and the group mean (diamond), and are shown as a function of cue type (drug cue vs. neutral cue) and the congruency of previous trial (previous congruent vs. previous incongruent) for the methamphetamine group (MA, left) and the healthy control group (HC, right). ***\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001, *\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8292739/v1/c623f0a60c05947fb5a63137.png"},{"id":104739993,"identity":"1c931d38-06f2-4fac-9b5e-0a66217b4357","added_by":"auto","created_at":"2026-03-16 16:14:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2031590,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8292739/v1/f0c4275f-1dc7-4360-8137-cefa96e25855.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Drug Cue Enhances Response Conflict and Reduces Conflict Adaptation in Methamphetamine Addiction","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn daily life, we often respond to information from different sources in our environment. While the automatic responses learned through repeated stimulus-response associations bear the advantage of being fast and effortless, they can nevertheless be interfering and hence have to be overcome when they are in conflict with the response required by the task goal. For instance, getting used to the touchpad of one laptop facilitates the communication with that laptop, but the habitual touchpad responses would lead to mistakes when switching to a laptop with a different touchpad rule. Cognitive control needs to be recruited in such contexts to resolve the response conflict, suppressing the inappropriate automatic responses and implementing the goal-directed responses (see Badre, \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2025\u003c/span\u003e for a recent review). The efficient resolution of response conflict by cognitive control is a key feature of cognitive flexibility, and the dysfunction of cognitive control characterizes maladaptive behaviors such as addiction and obsessive-compulsive disorder (Chambers et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Vandaele \u0026amp; Ahmed, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Wang et al., \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2024\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCognitive control is typically studied with tasks involving response conflict such as Go/NoGo, Stroop, Flanker and Simon tasks, where different responses are associated with different features of a presented stimulus. For instance, in the Stroop-like task (Stroop, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e1935\u003c/span\u003e), a word is presented where the meaning and the ink color of the word refer to the same color (e.g., a word text \u0026lsquo;red\u0026rsquo; in red) or different colors (e.g., a word text \u0026lsquo;red\u0026rsquo; in green) while the task is to make discriminative responses to the ink color with different buttons. The behavioral response is interfered with when the meaning and the ink color of the word are incongruent with each other relative to when they are congruent, resulting in slowed response times (RTs) and/or increased error rates (Cohen et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e1990\u003c/span\u003e; De Houwer, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2003\u003c/span\u003e). In a typical Simon task, a target is presented in either the left or right visual field, which induces an automatic response at the spatially corresponding hand (Simon, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e1969\u003c/span\u003e; Hommel, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). The response hand required by the task goal (e.g., left hand for a red target and right hand for a blue target) is facilitated when its response code converges with the spatial code of the target (both left or both right), whereas it is slowed down when the two response codes are in conflict with each other (left target, right response hand or right target, left response hand), resulting in the Simon effect (Zhang \u0026amp; Kornblum, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e1997\u003c/span\u003e; Proctor et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Salzer et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2017\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCognitive control can be measured not only by different performances between congruent and incongruent conditions in conflict tasks (i.e., the conflict effect), but also by conflict adaptation, where the conflict effect after an incongruent trial is smaller than after a congruent trial (Gratton et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e1992\u003c/span\u003e). While the phenomena of conflict effect and conflict adaptation have been widely observed, different accounts have been proposed to explain the mechanism (Botvinick et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2001\u003c/span\u003e; Hommel et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Verguts \u0026amp; Notebaert, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Chen et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Egner, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). The conflict-monitoring account highlights the top-down control in the prefrontal cortex in overcoming the conflict (Botvinick et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2001\u003c/span\u003e; Blais et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2007\u003c/span\u003e). The competing response tendencies activated in an incongruent condition are detected by the anterior cingulate cortex, which up-regulates the lateral prefrontal cortex to overcome the inappropriate response activation and resolve the conflict. The level of cognitive control is higher following an incongruent trial than following a congruent trial, leading to stronger inhibition on the inappropriate response activation and hence reduced conflict effect. The account of stimulus-response learning highlights the associations between the stimulus and the response in triggering the conflict effect and the conflict adaptation (Hommel et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Verguts \u0026amp; Notebaert, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Bustamante et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). A typical conflict task involves two stimulus-response associations: the task-relevant association (e.g., the association between left hand and a red target in the Simon task) and the task-irrelevant association (e.g., the association between right hand and a target on the right). The task-irrelevant association is enhanced after a congruent trial, which facilitates the response to the following congruent trial whereas delays the response to the following incongruent trial. By contrast, the task-irrelevant association is weakened after an incongruent trial, which facilitates the response to the following incongruent trial whereas delays the response to the following congruent trial.\u003c/p\u003e \u003cp\u003eA growing body of evidence has shown that cognitive control can be modulated by reward, a crucial reinforcer and motivator of human behavior (Pessoa, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Krebs et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Braem et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Botvinick \u0026amp; Braver, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Kang et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Wang et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). On the one hand, it has been shown that the conflict effects in various tasks were reduced during the expectation of reward (Boehler et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Soutschek et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Kang et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). In line with the conflict-monitoring account, it has been suggested that reward enhances the top-down control in the prefrontal cortex, which prioritizes the task-relevant processing while inhibiting the task-irrelevant processing (Padmala \u0026amp; Pessoa, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Botvinick \u0026amp; Braver, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). On the other hand, however, it has been shown that the conflict effect was enlarged when the target was associated with reward (Freeman et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Wang et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). For instance, in a Simon task, Wang et al. (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2019\u003c/span\u003e) presented a target letter in the left or right visual field, and the task was to make discriminative responses to the identity of the lateral target with the left or right hand. Importantly, the target letter in each trial could either lead to a receipt of high monetary reward upon a quick and correct response, or a low monetary reward. Results showed that the spatial congruency effect was larger when the target was associated with high reward than when the target was associated with low reward (Wang et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). This reward-enlarged conflict effect cannot be incorporated into the top-down control account, which would have predicted an otherwise reduced conflict by reward. Instead, the reward-enlarged conflict effect is consistent with the account of stimulus-response learning, as the task-irrelevant association (the automatic response to the location of the target) can be reinforced by reward.\u003c/p\u003e \u003cp\u003eBeyond the reward-enlarged conflict effect, the stimulus-response learning account can also be applied to explaining the maladaptive behaviors of self-control disorders such as drug addiction. According to the neuropsychological model of drug addiction, the habitual drug seeking and use have been strengthened by the drug-induced rewarding effect and sensitization (i.e., increasing doses and more frequent use of drugs to reach the same drug effect over the course of addiction), resulting in impaired cognitive control (Robinson \u0026amp; Berridge, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e1993\u003c/span\u003e; Everitt \u0026amp; Robbins, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Vandaele \u0026amp; Ahmed, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Although the dysfunction of cognitive control in drug addiction has been well documented as overall poorer performance in conflict tasks relative to healthy controls (HC) (Smith et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Wang et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Zilverstand et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), it remains unclear if drug use leads to enhanced task-irrelevant association between the drug cue and the behavioral response. Here, we adopted the Simon task to test this hypothesis in populations with methamphetamine (MA) use disorder. Following the design of the previous studies (Wang et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), a picture of a drug cue or a neutral cue was presented on the left or right visual hemifield to induce the automatic response tendency at the spatially corresponding hand (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The task was to discriminate the color of the frame in which the picture was embedded, with the response hand either on the same side or the opposite side of the target location, rendering spatial congruency between the automatic task-irrelevant response tendency and the task-relevant response. We thus predicted that, relative to the neutral cue, the drug cue would trigger a stronger response tendency at the spatially corresponding hand and lead to a larger Simon effect between the congruent and incongruent conditions. Crucially, this enhanced response tendency and enlarged Simon effect would only be observed in participants with drug addiction, but not in the HC group. Moreover, we also investigated if and how the conflict adaptation of the Simon effect was dependent on the cue. We predicted that the Simon effect would be smaller following an incongruent trial than following a congruent trial in the HC group, regardless of whether there was a drug cue or neutral cue, i.e., a typical conflict adaptation effect. In the MA group, however, the conflict adaptation would be smaller (Li et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) or might even disappear for the drug cue relative to the neutral cue, as the long-term association between the drug cue and the response could override the transiently changed association from the previous trial.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eSample size was estimated with G*Power 3.0 (Faul et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2007\u003c/span\u003e) according to a previous study employing the reward-based Simon paradigm (Wang et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Specifically, a significant interaction between reward level and spatial congruency was observed in the previous study with an alpha\u0026thinsp;=\u0026thinsp;0.022 and an effect size of η\u003csup\u003e2\u003c/sup\u003e\u003csub\u003ep\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.248. Given the statistics in the previous study, a correlation among repeated measures\u0026thinsp;=\u0026thinsp;0.5 and a default setting of nonsphericity correction (ε\u0026thinsp;=\u0026thinsp;1), a sample size of 20 was required to achieve an expected power of 99%. Following this criterion while considering potential data exclusion, 22 patients (all males, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) with MA use disorder were included to complete the experiment. Patients were recruited from a male drug rehabilitation center, with the following inclusion criteria: 1) met the DSM-5 criteria for methamphetamine use disorder; 2) age 18 years or older; 3) normal vision and normal color vision; 4) right-handed. Patients were excluded if they had a history of neurological illness or had been diagnosed with any psychiatric disorder meeting the DSM-5 criteria other than nicotine use disorder.\u003c/p\u003e \u003cp\u003eTwenty-two healthy controls (HCs) were recruited from the general population. They were first screened to match the education level of the patients, and were then included with the following inclusion criteria: 1) males, with age 18 years or older; 2) no current diagnosis or history of any psychiatric disorder meeting the DSM-5 criteria; 3) normal vision and normal color vision; 4) right-handed. None of them had a family history of psychiatric disorder. All patients and HCs reported no acute physical disease or chronic neurological disease. Written informed consent was obtained from each participant before the experiment. The study was conducted in accordance with the principles of the Declaration of Helsinki, and was approved by the Ethics Committee of Shanghai University of Sport (No. 102772019RT044).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic characteristics of the two groups of participants (MA: methamphetamine use disorder, HC: healthy controls).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003estatistics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41.23 (8.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.74 (10.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003et\u003c/em\u003e(21)\u0026thinsp;=\u0026thinsp;0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.848\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYears of education (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.32 (2.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.32 (2.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003et\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal years of smoking (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20.04 (10.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.63 (9.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003et\u003c/em\u003e(21)\u0026thinsp;=\u0026thinsp;3.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal years of alcohol drinking (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16.55 (12.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.14 (8.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003et\u003c/em\u003e(21)\u0026thinsp;=\u0026thinsp;2.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal years of substance use (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10.91 (6.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbstinent duration in months (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19.82 (9.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStimuli and Experimental Design\u003c/h3\u003e\n\u003cp\u003eStimuli were 24 pictures of MA-related scenes (drug cue) and 24 pictures of daily-life decorative accessories unrelated to any drug (neutral cue). Stimuli were presented against a black background on a laptop screen (34.5 * 19.5 cm). A white cross (0.5\u0026deg; * 0.5\u0026deg; of visual angle) was presented at the center of the screen as the central fixation. In each trial, a picture of either a drug cue or a neutral cue (2.4\u0026deg; * 2.4\u0026deg; of visual angle) embedded in a red or blue frame (2.6\u0026deg; * 2.6\u0026deg; of visual angle) was presented to the left or right of the central fixation (4.5\u0026deg; distance). The color of the frame was orthogonal to the cue type of the presented picture. Participants were required to discriminate the color of the frame (red vs. blue) by pressing the \u0026ldquo;z\u0026rdquo; or \u0026ldquo;m\u0026rdquo; button on the keyboard using their left or right index finger, respectively. Thus, the location of the presented picture was either congruent (the picture on the right embedded in a blue frame or the picture on the left embedded in a red frame) or incongruent (the picture on the right embedded in a red frame or the picture on the left embedded in a blue frame) with the required responding hand. Therefore, the experiment had a 2 (Group: MA vs. HC) * 2 (Cue Type: drug cue vs. neutral cue) * 2 (Spatial Congruency: congruent vs. incongruent) design. Participants were informed to pay attention to the color of the picture frame and respond as quickly and accurately as possible.\u003c/p\u003e\n\u003ch3\u003eProcedure\u003c/h3\u003e\n\u003cp\u003eParticipants were tested individually in a sound-attenuated environment. Each participant was seated in front of a laptop screen, and was required to fixate on the central fixation throughout each trial. The eye-to-screen distance was approximately 60 cm.\u003c/p\u003e \u003cp\u003eEach trial started with the presentation of the central fixation for a varying duration of 400/500/600/700 ms. The picture was then presented for 600 ms, followed by a blank screen which lasted up to 1900 ms until a response was given. Responses made after this time window were identified as omissions. The inter-trial interval was a blank screen of 1000 ms. There were 24 trials in each of the 4 experimental conditions. The 96 trials in total were mixed and divided into 4 blocks of equal length (24 trials). Trials from the 4 conditions were presented in a random order in each block. There was a break between each two blocks, the length of which was self-paced. To get participants familiar with the task, a short practice session of 8 trials was provided prior to the formal experiment. The pictures presented in the practice session were all neutral cues that were not presented in the formal experiment. The practice session was repeated if the response accuracy was below 75%.\u003c/p\u003e\n\u003ch3\u003eStatistical analysis of data\u003c/h3\u003e\n\u003cp\u003eFor each participant, omissions and trials with incorrect responses in each condition were excluded from data analysis. Mean reaction time (RT) of the remaining trials was then calculated for each condition. The error rate (ER) in each condition was calculated as the proportion of omissions and incorrect trials against the total trials in that condition. A 2 (Group: MA vs. HC) * 2 (Cue Type: drug cue vs. neutral cue) * 2 (Spatial Congruency: congruent vs. incongruent) repeated-measures ANOVA was conducted on the mean RT and the ER respectively, with Group as a between-subjects factor and Cue Type and Spatial Congruency as within-subject factors. The alpha level for rejecting a null hypothesis was set to 0.05. Paired \u003cem\u003et\u003c/em\u003e-tests were further conducted following a significant interaction.\u003c/p\u003e \u003cp\u003eTo investigate how the conflict adaptation was affected by the drug cue, trials in each condition were further sorted according to the congruency of the previous trial. The Simon effect, in terms of RT and ER difference between the incongruent condition and the congruent condition, was calculated for each of the four conditions: drug cue following a congruent trial, drug cue following an incongruent trial, neutral cue following a congruent trial, neutral cue following an incongruent trial (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). A 2 (Previous Congruency: congruent vs. incongruent) * 2 (Cue Type: drug vs. neutral) ANOVA was then conducted on the Simon effect for the MA group and the HC group, respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMean and standard errors (in parentheses) of reaction time (RT, ms) and error rate (ER, %) in each experimental condition and group (MA: methamphetamine use disorder, HC: healthy controls).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMeasurement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eDrug Cue\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eNeutral Cue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCongruent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIncongruent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCongruent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIncongruent\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e552 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e608 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e583 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e605 (15)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e551 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e591 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e559 (19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e609 (21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.5 (1.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.6 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.3 (1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7.4 (1.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.5 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.3 (1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.7 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13.1 (2.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eThe Simon effect\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes the mean RT and error rate in each condition of each group. The 2 (Group: MA vs. HC) * 2 (Cue Type: drug vs. neutral) * 2 (Congruency: congruent vs. incongruent) repeated-measures ANOVA on RTs showed a main effect of Cue Type, \u003cem\u003eF\u003c/em\u003e(1, 42)\u0026thinsp;=\u0026thinsp;8.46, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.168, indicating overall faster responses to the drug cue than to the neutral cue, a main effect of Congruency, \u003cem\u003eF\u003c/em\u003e(1, 42)\u0026thinsp;=\u0026thinsp;78.56, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.652, indicating overall faster responses to the spatially congruent cue than to the incongruent cue, i.e., a typical Simon effect. However, the main effect of Group did not reach significance, \u003cem\u003eF\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;1, indicating comparable RTs between the two groups. Importantly, there was a three-way interaction between Group, Cue Type, and Congruency, \u003cem\u003eF\u003c/em\u003e(1, 42)\u0026thinsp;=\u0026thinsp;8.49, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.168, whereas the two-way interactions did not reach significance, all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.1.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eGiven the three-way interaction, a 2 (Cue Type: drug vs. neutral) * 2 (Congruency: congruent vs. incongruent) repeated-measures ANOVA was conducted for MA and HC respectively. For MA, both the main effect of Cue Type, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;6.32, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.231, and the main effect of Congruency, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;34.91, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.624, were significant (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, left). Moreover, the interaction between Cue Type and Congruency was also significant, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;7.84, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.272. This interaction was due to a larger Simon effect induced by the drug cue (RT difference between congruent and incongruent conditions: 56 ms) than by the neutral cue (RT difference: 22 ms), Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.597, 95%CI [8.84, 59.90]. Further \u003cem\u003et\u003c/em\u003e-tests teasing apart the interaction showed that the drug cue induced faster responses than the neutral cue in the congruent condition (RT difference: 31 ms), \u003cem\u003et\u003c/em\u003e(21)\u0026thinsp;=\u0026thinsp;3.18, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005, Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.867, 95%CI [10.60, 50.86], whereas the responses to the two types of cues were comparable in the incongruent condition, \u003cem\u003et\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;1. The faster responses to the drug cue than the neutral cue in the congruent condition also manifested at the individual level, as 17 out of 22 MA participants showed this pattern, whereas there was no such clear pattern in the incongruent condition, with 10 out of 22 MA participants responding faster to the drug cue than the neutral cue (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, left).\u003c/p\u003e \u003cp\u003eFor HC (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, right), the main effect of Cue Type was not significant, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;3.05, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.095, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.127; the main effect of Congruency was significant, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;43.76, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.676. However, the interaction between Cue Type and Congruency did not reach significance, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;1.16, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.293.\u003c/p\u003e \u003cp\u003eThe three-way ANOVA on the ER showed a main effect of Cue Type, \u003cem\u003eF\u003c/em\u003e(1, 42)\u0026thinsp;=\u0026thinsp;4.20, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.091, indicating overall lower error rates to drug cue than neutral cue, a main effect of Congruency, \u003cem\u003eF\u003c/em\u003e(1, 42)\u0026thinsp;=\u0026thinsp;9.30, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.181, indicating overall lower ER to spatially congruent cue than incongruent cue, and a main effect of Group, \u003cem\u003eF\u003c/em\u003e(1, 42)\u0026thinsp;=\u0026thinsp;5.00, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.106, indicating lower ER in the MA group than in the control group. However, none of the two-way interactions reached significance, all \u003cem\u003eF\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;1. The three-way interaction did not reach significance either, \u003cem\u003eF\u003c/em\u003e(1, 42)\u0026thinsp;=\u0026thinsp;3.00, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.090. Therefore, the results of ER did not show the opposite pattern to the results of RT, ruling out that the observed effects based on RT was due to potential speed-accuracy trade-off.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMean and standard errors (in parentheses) of Simon effect, in terms of RT difference (ms) and ER difference (%) in each condition and group (MA: methamphetamine use disorder, HC: healthy control).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMeasurement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eDrug Cue\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eNeutral Cue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePrevious Congruent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePrevious\u003c/p\u003e \u003cp\u003eIncongruent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePrevious Congruent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePrevious\u003c/p\u003e \u003cp\u003eIncongruent\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 (9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e37 (10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-7 (11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74 (15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e77 (20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e33 (13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eER\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.4 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.9 (1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.3 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-1.3 (2.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.7 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-2.9 (3.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.1 (2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.2 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eThe conflict adaptation of the Simon effect\u003c/h3\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e summarizes the size of the Simon effect in each condition. For the MA group, the main effect of Previous Congruency was significant, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;7.92, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.274, indicating a larger Simon effect following a congruent trial than following an incongruent trial, i.e., a typical conflict adaptation. The main effect of Cue Type was significant, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;10.89, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.341, indicating a larger Simon effect for a drug cue than for a neutral cue (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, left). Importantly, the interaction between Previous Congruency and Cue Type was also significant, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;6.29, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.231. Further \u003cem\u003et\u003c/em\u003e-tests teasing apart the interaction showed that the conflict adaptation was observed only for the neutral cue (Simon effect: 37 ms following a congruent trial vs. -7 ms following an incongruent trial), \u003cem\u003et\u003c/em\u003e(21)\u0026thinsp;=\u0026thinsp;3.95, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.842, 95%CI [20.72, 66.80]. For the drug cue, however, the Simon effect following a congruent trial (59 ms) was statistically equivalent to the Simon effect following an incongruent trial (49 ms), \u003cem\u003et\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;1. This null effect was further verified by the Bayes factor analysis (Wagenmakers, Marsmann et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), showing that the null hypothesis \u0026ldquo;the Simon effect following a congruent trial did not differ from the Simon effect following an incongruent trial\u0026rdquo; was 3.33 times (\u0026gt;\u0026thinsp;3 as moderate evidence, Wagenmakers, Love et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) more likely to be true than the alternative hypothesis that \u0026ldquo;the Simon effect following a congruent trial was different from the Simon effect following an incongruent trial\u0026rdquo;.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFor the HC group, the two-way ANOVA revealed only a significant main effect of Previous Congruency, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;16.71, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.443, whereas neither the main effect of Cue Type, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;1.04, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.320, nor the interaction, \u003cem\u003eF\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;1, reached significance, indicating comparable conflict adaptation effects for the drug cue and the neutral cue (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, right).\u003c/p\u003e \u003cp\u003eSimilar analyses were performed on the Simon effect based on ER. For MA, the two-way ANOVA showed only a significant main effect of Previous Congruency, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;10.89, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.342, indicating a larger Simon effect following a congruent trial than following an incongruent trial, i.e., a typical conflict adaptation. However, neither the main effect of Cue Type, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;1.02, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.324, nor the interaction, \u003cem\u003eF\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;1, reached significance. For HC, the results showed the same pattern: the main effect of Previous Congruency was marginally significant, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;3.78, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.066, \u003cem\u003eη\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.152, whereas neither the main effect of Cue Type, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;1.58, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.222, nor the interaction, \u003cem\u003eF\u003c/em\u003e(1, 21)\u0026thinsp;=\u0026thinsp;1.91, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.182, reached significance.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study, we adopted a modified Simon task to investigate if there was an enhanced task-irrelevant association between the drug cue and the automatic response at the spatially congruent hand in individuals with drug addiction. We tested this hypothesis both by comparing the Simon effects induced by the drug cue versus neutral cue, and by examining the adaptation effects of the Simon conflict in the presence of the drug cue versus neutral cue. The results showed that the MA group exhibited a significantly larger Simon effect for the drug cue compared to the neutral cue, whereas the Simon effects in the HC group were equivalent between the drug-cue condition and the neutral-cue condition. Further tests showed that the enlarged Simon effect was due to significantly facilitated responses by the drug cue than the neutral cue in the congruent condition. Moreover, the adaptation effects of the Simon conflict in the HC group were equally observed for both the drug cue and the neutral cue, with a smaller Simon effect following an incongruent trial than following a congruent trial. In the MA group, however, such adaptation effect occurred only for the neutral cue but not for the drug cue. When responding to the drug cue, the Simon effects were comparable regardless of whether the previous trial was congruent or incongruent. The convergent evidence consistently confirmed the enhanced association between the automatic response tendency and the task-irrelevant location of the drug cue, resulting in the overall enlarged Simon effect and reduced conflict adaptation.\u003c/p\u003e \u003cp\u003eThe present observations are consistent with existing findings showing that the response conflict can be enlarged by reward (Krebs et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; Freeman et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Wang et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Wang et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). For instance, in a Stroop task where discriminative responses were required among 4 alternative colors of the presented word, correct and fast responses to two colors were associated with (reward-related colors) whereas responses to the other two colors were not associated with reward (reward-unrelated colors) (Krebs et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). While the performance was generally enhanced in responding to reward-related colors relative to reward-unrelated colors, the word meaning referring to the reward-related color led to stronger interference and hence larger Stroop conflict than the word meaning referring to the reward-unrelated color. These results suggested that the association between a task-relevant feature (i.e., color) and the corresponding response transferred to the task-irrelevant feature (i.e., word meaning). Similarly in a Simon task where correct and fast responses to the target letter were associated with high- or low-reward, the automatic response to the location of the high-reward target was facilitated more than the low-reward target, resulting in a reward-enlarged Simon effect (Wang et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). In an extension of these findings, the current results provide evidence from clinical populations that people with drug addiction, who had long-term experience associating drug cues with the rewarding effects of drug use, exhibited a stronger response tendency to the task-irrelevant feature of the drug cue relative to the neutral cue.\u003c/p\u003e \u003cp\u003eEvidence also comes from the reward-modulated conflict adaptation effect (Braem et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Sturmer et al., 2011). For instance, in a Simon task where only the responses with the first percentile of speed were associated with monetary gain, the adaptation effect of the Simon conflict was larger following a reward trial than a no-reward trial (Sturmer et al., 2011). The enhanced conflict adaptation after a reward trial than after a no-reward trial was also observed in a flanker task, suggesting that reward strengthened the stimulus-response association (Braem et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). One may note that the reward-enlarged conflict adaptation effects in these studies appear to be in contrast to the reduced conflict adaptation by the drug cue in the present study. However, it should be noted that, in these previous studies, reward was not associated with any particular stimulus but with the response in a particular trial, rendering a transiently enhanced task-relevant association. Relative to a congruent trial, the reward-enhanced association between the stimulus and response in an incongruent trial thus facilitated the response in the next trial when it was also incongruent (i.e., unchanged stimulus-response mapping) whereas delayed the response when it was congruent (i.e., changed stimulus-response mapping). By contrast, in the present study, we focused on how the adaptation effect was affected by the reward significance of the stimulus in the current trial but not the reward significance of the response in the previous trial. The long-term drug use resulted in a sustained stronger stimulus-response association specific to the drug cue but not the neutral cue in the MA group, which in turn was immune to the transient change of the association from the previous trial and led to comparable Simon effects.\u003c/p\u003e \u003cp\u003eAlong with the collective evidence of the reward-modulated response conflict and the conflict adaptation in the above-mentioned studies, the enlarged Simon effect and reduced conflict adaptation by the drug cue in the present study cannot be simply accounted for by the top-down control mechanism. Specifically, it has been suggested that reward can enhance the top-down control in the prefrontal cortex, which prioritizes the task-relevant processing while inhibiting the task-irrelevant processing (Padmala \u0026amp; Pessoa, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Botvinick \u0026amp; Braver, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). From this perspective, the response conflict would have been lower and the adaptation effect would have been larger at the presence of a reward-predictive stimulus. These findings thus support the account of the stimulus-response learning (Hommel et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Verguts \u0026amp; Notebaert, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Chen et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) in the way that the strengthened association between a response to a reward-predictive stimulus can transfer to the other features of this stimulus and enhance the task-irrelevant response tendencies. Although our findings clearly suggest a role of the stimulus-response learning in the response conflict and conflict adaptation, it does not mean that the top-down control mechanism was not present at all. In the previous study of the reward-enhanced Simon effect, the functional connectivity between the pre-supplementary area and the right inferior frontal cortex was more strongly recruited to cope with the reward-enhanced response conflict (Wang et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Taken together, these results suggest that cognitive control acts as a coordinated system of stimulus-response learning and top-down control (Bustamante et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Ritz et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur findings agree with recent studies using other approaches to manipulate the stimulus-response associations (Chen et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Zhang et al., \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Held et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Li et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). For instance, in a Simon task, reward was presented only after correct and fast responses to congruent trials for one group of participants (RC group), was presented only after correct and fast responses to in congruent trials for another group of participants (RI group), and was equally presented after correct and fast responses to both types of trials for a third group of participants (neutral group) (Chen et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Results showed that, relative to the neutral group, the Simon effect was increased in the RC group and was even reversed in the RI group, with faster responses in the incongruent trials than in the congruent trials. These results suggested that reward enhanced the congruent stimulus-response associations in the RC group and enhanced the incongruent stimulus-response associations in the RI group, which added to and overridden the original, reward-neutral stimulus-response associations, respectively (Chen et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Notably, in the initial learning stage (e.g., the first two blocks) of the same study, the learning effects were more prominent in the RC condition than the RI condition (Chen et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). In another study where a Stroop task was adopted, selectively presenting reward after responses to incongruent trials only led to a weak reduction of the conflict effect, whereas selectively presenting reward after responses to congruent trials led to a strong increase of the conflict effect (Prevel et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Collectively, these results suggested a biased learning effect for the automatic stimulus-response associations, which also helps to explain why the enlarged Simon effect was dominated by the fast response to the drug cue in the congruent condition.\u003c/p\u003e \u003cp\u003eOur findings also provide new insights into the dysfunctional cognitive control in drug addiction. In a traditional view, the deficits are understood as a dysfunction of the top-down inhibitory control governed by the fronto-striatal pathway in the brain, where the dopamine-mediated regulation has been disrupted by drug use, resulting in overall lowered performance in conflict tasks (Smith et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Wang et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Zilverstand et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). However, the observed effects here cannot be simply due to an impaired function of top-down inhibitory control, as the MA group did not show overall lowered task performance relative to the HC group. Specifically, the overall RTs were comparable between the two groups, and the overall ER was even lower in the MA group than the HC group in both the congruent and incongruent conditions. In addition, the conflict adaptation was still observed for the neutral cue in MA, suggesting that the observed effects were specific to the drug cue rather than an overall changed ability of cognitive control. The observed effects thus occur mainly at the cost of the dominant automatic response tendency to the drug-related stimuli.\u003c/p\u003e \u003cp\u003eOne limitation of the present study is that only male participants were included in both the MA group and hence the matched HC group. Although to our knowledge there is no fundamental sex difference in either the general Simon effect or the reward-modulated Simon effect (Wang et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2019\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), the generalization of the present findings to female participants still needs to be verified.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003e In summary, the present study showed that, relative to a neutral cue, a drug cue induced an enlarged spatial response conflict (i.e., Simon effect) in MAs, whereas the conflict effects were comparable for the drug cue and the neutral cue in HCs. Moreover, while both cues induced comparable adaptation effects of the response conflict in HCs, the drug cue reduced the adaptation effect relative to the neutral cue in MAs. The results suggest enhanced task-irrelevant drug cue-response association in MAs and shed light on the mechanism of impaired cognitive control in drug addiction.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Dr. Zhongbin Su for the data illustrations. This study was supported by the National Natural Science Foundation of China (No. 32000779) and the Fundamental Research Funds for Central Universities (No. YG2025QNB13) to LW.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor contribution\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eL.W. conceived and designed the study, Y.X. collected and analyzed the data, L.W. and Y.L. supervised the project, L.W. and Y.X. wrote the original draft, L.W., Y.X. and Y.L. revised and approved the final manuscript.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData of the present study has been deposited at OSF, accession code: osf.io/5c4bk/.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBadre, D. 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Neuroimaging Impaired Response Inhibition and Salience Attribution in Human Drug Addiction: A Systematic Review. \u003cem\u003eNeuron\u003c/em\u003e, \u003cem\u003e98\u003c/em\u003e(5), 886\u0026ndash;903. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.neuron.2018.03.048\u003c/span\u003e\u003cspan address=\"10.1016/j.neuron.2018.03.048\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"psychological-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prpf","sideBox":"Learn more about [Psychological Research](http://link.springer.com/journal/426)","snPcode":"426","submissionUrl":"https://submission.nature.com/new-submission/426/3","title":"Psychological Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"drug addiction, response conflict, conflict adaptation, Simon effect","lastPublishedDoi":"10.21203/rs.3.rs-8292739/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8292739/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe stimulus-response learning account of cognitive control suggests that conflict between a task-relevant response and a task-irrelevant interfering response is contingent upon the stimulus-response associations, the strength of which can be reinforced by rewarding experience. Here, we employed a modified Simon task to investigate if patients with methamphetamine use disorder (MA) exhibited enhanced association between drug-related cues and task-irrelevant responses compared to healthy controls (HC). A lateral picture of a drug cue or a neutral cue was presented in either the left or right visual hemifield, which triggered an automatic response tendency at the spatially corresponding hand. Participants discriminated the color of the frame enclosing the cue, with responses either congruent or incongruent with the cue. Relative to the neutral cue, the drug cue induced a stronger response tendency at the spatially congruent hand in MA, and hence a larger interference when this response tendency was incongruent with the task-required hand (i.e., Simon effect). In contrast, the two cues induced comparable Simon effects in HC. Moreover, in MA, the Simon effect was smaller after an incongruent trial than after a congruent trial only for the neutral cue (i.e., conflict adaptation), but not for the drug cue. However, the conflict adaptation effects were equally observed for both cues in HC. These results suggest a MA-specific enhanced association between the drug cue and the task-irrelevant response. Our findings extend the theoretical scope of cognitive control into the clinical context, and provide new evidence in understanding the dysfunctional cognitive control in drug addiction.\u003c/p\u003e","manuscriptTitle":"Drug Cue Enhances Response Conflict and Reduces Conflict Adaptation in Methamphetamine Addiction","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-16 15:03:00","doi":"10.21203/rs.3.rs-8292739/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-30T01:17:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-22T16:19:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-07T22:05:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"72618444777051954421198436128794741580","date":"2025-12-11T15:55:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"32692486346502536681302448130212614803","date":"2025-12-11T12:17:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-11T11:46:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-09T13:32:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-08T10:48:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"Psychological Research","date":"2025-12-06T07:05:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"psychological-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prpf","sideBox":"Learn more about [Psychological Research](http://link.springer.com/journal/426)","snPcode":"426","submissionUrl":"https://submission.nature.com/new-submission/426/3","title":"Psychological Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d55108c6-12d1-4da4-af7c-3b43f6467a9e","owner":[],"postedDate":"December 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-16T16:09:25+00:00","versionOfRecord":{"articleIdentity":"rs-8292739","link":"https://doi.org/10.1007/s00426-026-02277-7","journal":{"identity":"psychological-research","isVorOnly":false,"title":"Psychological Research"},"publishedOn":"2026-03-12 15:59:44","publishedOnDateReadable":"March 12th, 2026"},"versionCreatedAt":"2025-12-16 15:03:00","video":"","vorDoi":"10.1007/s00426-026-02277-7","vorDoiUrl":"https://doi.org/10.1007/s00426-026-02277-7","workflowStages":[]},"version":"v1","identity":"rs-8292739","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8292739","identity":"rs-8292739","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}