Immediate and lasting effects of different regulation of craving strategies on cue‐induced craving and the late positive potential in smokers

Craving, induced by substance‐related cues, contributes to continued substance use and relapse. Therefore, regulation of craving (ROC) is important for treatment success. Distraction involves disengaging from craving‐inducing cues; whereas, reappraisal requires engaging with potential risks of substance use. Given this difference in elaboration, we addressed the question whether reappraisal entails lasting advantages over distraction in successful ROC. To elucidate how this is implemented neurally, we examined the late positive potential (LPP) as an electrocortical indicator of motivated attention to cues. N = 62 smokers viewed smoking‐related pictures and indicated the degree of craving each picture induced. While viewing the pictures, EEG was recorded, and the participants focused on the long‐term negative (LATER) or short‐term positive (NOW) consequences of smoking or performed an arithmetic task to distract themselves from processing the pictures (DISTRACT). After a break, all pictures were presented again without regulation instruction (re‐exposure). Results revealed that LATER and DISTRACT achieved similar degrees of immediate ROC success, but only LATER had a sustained effect during re‐exposure. In contrast, LPP amplitudes were more prominently reduced during DISTRACT than LATER, and there was no difference in LPP amplitudes during re‐exposure. These findings imply that it may be beneficial to engage with the risks of drug use (reappraisal) rather than avoiding triggers of craving (distraction). However, these effects do not seem to be mediated by lasting changes in cue‐related motivated attention (LPP).

An important factor for abstinence is craving, as it has been shown to predict use and relapse. 4,5 Craving is part of the diagnostic criteria for SUDs, which can be defined as being consciously aware of the urge to use a substance, 6,7 measured as the subjective intensity of the perceived urge to use a particular substance 7 and linked to neural activity of reward-related brain areas like the ventral striatum or orbitofrontal cortex. 8 It can be induced by substance-related cues (e.g., pictures), which signal future drug reward because of repeated coupling with substance use. 7 Furthermore, substance-related cues are discussed as taking over the incentive salience of drugs and triggering drug use even when drugs themselves are no longer rewarding. 9 As encounters with substance-related cues and craving are common in daily life, they can explain sustained drug use even when this stands in conflict with other goals specified in a situation without cue-induced craving. 10,11 Therefore, managing cue-induced craving is an important part of SUD treatment. 10 A promising treatment approach is cognitive regulation of craving (ROC). This is especially important in situations when there are no options to avoid substance-related cues and craving. 12 The concept of ROC is based on the findings regarding emotion regulation (ER), and there are similarities between affect and craving (physiology, behaviour and subjective experience). 12,13 Various strategies have been shown to successfully regulate emotions by changing the deployment of attention or the appraisal of the emotion-triggering stimuli. 13 Often used strategies are reappraisal, that is, to change the meaning of a stimulus, and distraction, that is, to avoid the deeper elaboration of a stimulus. 14,15 Similar strategies have been examined regarding cue-induced craving in SUD. The ROC paradigm by Kober and colleagues 16,17 employed a strategy aiming to diminish the incentive value of smoking by instructing participants to focus on the long-term negative consequences compared with the short-term benefits of smoking while viewing smoking-related cues. 16,17 The ROC paradigm also proved successful for alcohol, cocaine and methamphetamine cues [18][19][20][21] and yielded reduced activity in craving-related brain regions. 17,21 Whereas the effects of anticipating long-term costs are well examined, the effects of distraction on craving have received less attention. Lopez and colleagues 22 trained smokers who are motivated to quit smoking in either of the two strategies. They found that the number of cigarettes smoked per day decreased significantly for up to 1 month after the intervention for both strategies; whereas, no differences between the strategies emerged. They found no difference between focusing on the long-term risks of smoking and distraction. However, Moore and colleagues 5 found that individuals who used distraction to manage craving were at increased risk for relapse, raising the question whether there are longer-term differences between the strategies. ER research found differences between lasting effects of distraction compared with reappraisal and passive viewing on neural processing of emotional pictures. 15,23 Electroencephalography (EEG) offers the opportunity to examine cue and motivational processes in a timesensitive fashion with event-related potentials (ERPs). One ERP related to ER is the late positive potential (LPP). 24 The LPP emerges at around 300 ms after stimulus onset with a centro-parietal distribution and continues throughout visual stimulus presentation and beyond. 25,26 It is thought to reflect attentional allocation towards motivationally significant stimuli, with more positive LPP amplitudes in response to emotional compared to neutral stimuli. [25][26][27] The LPP is higher in individuals diagnosed with SUD, in response to substance-related versus neutral pictures. 28 Likewise, the LPP for smoking cues is higher in current compared with former or nonsmokers and has been linked to craving. 29,30 Furthermore, the LPP is sensitive to ROC and can be manipulated by focusing on different motivational aspects of substance cues. [31][32][33] Meule and colleagues 32 examined food craving and found higher amplitudes of the early LPP (350-550 ms) when participants focused on long-term negative consequences compared with short-term benefits of low and high caloric food. They interpreted the increase of the LPP to reflect higher arousal due to negative imagery inherent to long-term negative consequences. Distraction was found to be accompanied by decreased LPP amplitudes, consistent with the shift in attention allocation away from the stimulus. 31 Lasting effects on LPP amplitudes have only been examined in ER. It was shown that negative images previously subject to distraction elicited higher LPP amplitudes upon later re-exposure than images previously subject to passive attention or reappraisal. 15,23 Thus, distraction does not seem to have a lasting effect, whereas there are mixed findings for reappraisal, sometimes showing an advantage and sometimes finding no advantage over a passive viewing condition. 15,34,35 The lasting effects of regulating cue-induced craving by thinking of the future negative consequences of smoking (e.g., fear of developing cancer) are unknown and have yet to be compared with the lasting effects of distraction. Lasting ROC effects are particularly relevant in SUDs as they may prevent repeated exposure to high cueinduced craving and high risk of relapse. Therefore, our aim was to study the differences in the lasting effects of the two strategies to regulate craving: distraction and focusing on negative aspects of substance-use. We compared the strategies regarding their impact on subjective craving and neural stimulus processing, which we examined during regulation, for immediate effects, as well as during re-exposure, for lasting effects. Based on prior results, we expected that focusing on long-term costs (LATER) and distraction (DISTRACT) would result in lower subjective craving compared with focusing on the short-term benefits of smoking (NOW). 16,22 A subsample (n = 27) of the study has been used to examine the single-trial correlates of ROC and the differences between regulation conditions. 36 Although our initial hypothesis was that compared with NOW, DISTRACT should reduce LPP amplitudes whereas LATER should increase LPP amplitudes, 31,32 we observed reduced LPP amplitudes for both. 36 Thus, we re-examined this effect in the larger sample. The main question of the current study was whether the strategies for the ROC differentially affected craving and LPP during re-exposure and has not been examined in a previous report. 36 For cues previously associated with DISTRACT, we predicted a level of subjective craving and LPP amplitude upon re-exposure comparable to the one for cues previously subject to the NOW instruction. 5,15,23 As the LATER strategy reduces craving through an elaborate effort targeting the desire to smoke, we expected that craving and LPP amplitudes should be reduced for cues previously associated with the LATER as compared with the NOW instruction.

| Sample
We recruited smokers from the general population via advertisement on Facebook, e-mailing lists and flyers and asked them to fill out a short online survey regarding their contact information and the number of smoked cigarettes per day. Potential participants were contacted by telephone and interviewed about inclusion criteria. We used sections of the DSM 5 Clinical Version (SCID-5-CV) to assess the SUD criteria and SCID screening questions for other mental disorders. 37 The inclusion criteria were smoking at least eight cigarettes per day for at least one-year, fulfilling a minimum number of two DSM-5 criteria for TUD, fluency in German and normal or corrected-to-normal vision. Exclusion criteria were current plans to quit smoking, psychoactive medication within the past 3 months, >4 past or present DSM-5 criteria of alcohol use disorder or cannabis use disorder (if one of them has withdrawal syndrome or uses substance despite substance-related physical or psychological problems, >1 criteria were enough to be excluded), regular use of other drugs and any other past or present psychological disorder apart from depression and anxiety (only excluded if present within the last 3 months). Sample size estimation was conducted for t-test, examining the difference between dependent means with power (1 À β) = 0.80 and α = 0.05 using G*Power 3.1, 38 focusing on the comparison of distraction and short-term benefits during re-exposure.
Assuming dz ≈ 0.32 for this effect based on previous works, 15,23 the necessary sample size was n = 62. After screening, N = 70 smokers participated. For our analysis, n = 8 participants were excluded (n = 3 due to erroneous inclusion during recruitment, n = 3 due to nonresponding to cues [mean craving rating <10 in the NOW condition], n = 1 did not understand the task and n = 1 fell asleep during the task) leaving n = 62 (31 female) for analysis. Sample characteristics can be found in Table 1 and in Supplementary Material S1.
Participants were asked to abstain 3 h from smoking, 24 h from alcohol and 1 week from cannabis use prior to testing. Abstinence from smoking was confirmed with a carbon monoxide breath test (Micro 4 Smokerlyzer Bedfont), of which participants were informed beforehand to ensure compliance with the abstinence duration. The study protocol was approved by the local ethics committee (reference number EK 53022018). All participants provided informed consent in accordance with the Declaration of Helsinki and received 30€. A subsample of n = 27 participants was analysed before to investigate craving-related EEG activity. 36

| ROC task
We used an adaptation of the ROC task (see Figure 1), including a regulation phase and, important for our research question, a re-exposure phase. 16 During the regulation phase, after a central fixation cross  'Y -X À X'; e.g., 317 -11 À 11). NOW, LATER and DISTRACT instructions were followed by pictures with smoking content. Three sets of 20 smoking pictures, taken from prior sources [39][40][41] were created comparable in ratings of arousal, valence and craving, as well as in terms of content. 36 The mapping of sets to each instruction was balanced across participants. The instruction to attend to the picture was followed by a set of 20 neutral pictures of everyday items taken from the International Affective Picture System (IAPS). 42 After the picture presentation, participants were asked to rate their craving for smoking while viewing the picture on a visual analogue scale (VAS; 'none at all'-'very strong') using the computer mouse wheel. The regulation phase was divided into three blocks, each containing 80 trials during which the four sets of 20 pictures for each of the four conditions were shown. Thus, in line with prior work, participants viewed each picture three times with the same instruction. 23 Within each block, trial order was pseudorandomized, and each condition was not shown more than twice in a row. Following the regulation phase, there was a 10-minute break for the participants before the re-exposure phase started. 23 The re-exposure phase was not announced to the participants in advance and consisted of one block in which participants viewed all 80 pictures again without regulation instructions (trial timing was otherwise identical) and rated their craving after each picture.   43 We applied low and high pass filters with cut-offs at 30

| Behavioural results
Mean craving ratings for regulation and re-exposure are displayed in General craving (analysed for n = 61, data from n = 1 were lost because of technical issues) changed over time. The repeatedmeasures ANOVA revealed a significant effect for time, F (2) = 7.68, p = 0.002, η 2 p = 0.11. Post-hoc t-tests revealed an increase over time from before to after regulation, t(60) = 2.96, p = 0.009, d z = 0.38, that persisted after re-exposure (no difference between after regulation and after re-exposure, p = 0.910; before regulation vs. after reexposure: t(60) = 3.03, p = 0.011, d z = 0.39).

| ERP results
LPP time course and topographies can be found in Figure 3.  Table 2. During regulation, the LPP in the DISTRACT condition was significantly lower than the LPP for LATER and NOW but did not differ significantly from NEUTRAL. The LPP during LATER was significantly higher than NEUTRAL but lower than the LPP during NOW, which revealed the highest LPP amplitude. During reexposure, the LPP for NEUTRAL was lower than for all other conditions, but there were no differences between the LPPs evoked by smoking picture sets previously connected to NOW, DISTRACT and LATER. In parallel with behavioural analysis, we also compared the between-phase change in LPP between LATER and DISTRACT.
This difference (re-exposure minus regulation) was significantly F I G U R E 2 Mean craving ratings and late positive potential (LPP) amplitudes per condition and phase. On the left side, mean craving ratings for NOW, DISTRACT, LATER and NEUTRAL are shown during regulation (in blue) and during re-exposure (in grey). General craving is shown under PrePost for before regulation (in blue) and after re-exposure (in grey). On the right side, mean LPP amplitudes for NOW, DISTRACT, LATER and NEUTRAL are shown during regulation (in blue) and during re-exposure (in grey). smaller in LATER, t(61) = À5.37, p < 0.001, d z = À0.68, which was because of larger LPP amplitudes for the LATER condition during regulation.
To explore potential differences in effects on LPP amplitude over time, we conducted an exploratory repeated-measures ANOVA contrasting the within-subjects factors strategy and phase as well as time window (300-1000, 1000-2000, 2000-3000 and 3000-4000) to assess potential temporal dynamics of the LPP. 14,45 Results can be found in the Supplementary Material S4.

| DISCUSSION
The aim of this study was to compare two cognitive strategies for regulating craving (focusing on long-term costs of use and distraction) in terms of their immediate and potential lasting effects on cue-induced craving and neural stimulus processing (indicated by the LPP). As expected, we found that both strategies successfully reduced craving and that this immediate regulatory success of both strategies is comparable. The results regarding subjective craving were accompanied by lower LPP amplitudes for both strategies during the regulation phase, with the lowest LPP for DISTRACT.
Importantly, in the re-exposure phase, subjective craving increased, but was lower for pictures that were previously presented with the instruction LATER compared with NOW and DISTRACT; whereas, no lasting reduction of craving was found for the pictures that were presented with the DISTRACT instruction before. However, this effect was not observable for the LPP, which was larger for cigarette pictures than for neutral pictures, regardless of the strategy previously used.
With respect to the regulation phase, these results are consistent with previous research. We found DISTRACT and LATER to be similarly successful in immediate ROC. This stands in line with results from ER research showing similar regulation effects for both strategies, 14 but differs from results that showed higher regulatory success of reappraisal compared with distraction. 15,35 Regarding ROC, it confirms the results from Lopez and colleagues, 22 who found no difference between two groups using either of the strategies to reduce smoking.
The current study extends these findings to smokers that were not motivated to quit and to a within-subjects comparison, which should be more sensitive to the differences between conditions. Motivation to quit can be important as having this goal could affect the evaluation (i.e., aversive) of smoking-related cues. 46 By excluding smokers with a motivation to change, our findings are a good proxy for the status of individuals before starting to change smoking behaviour.
Regarding the mechanisms of regulation strategies, our results show that DISTRACT is accompanied by reduced LPP amplitudes, which indicates reduced attention towards the cues. This resembles distraction effects in the LPP during ER, which are interpreted such that distraction works by preventing deeper processing of the cues and, therefore, prevents the stimulus from acquiring greater significance for the viewer. 13-15 LATER compared with NOW serves to decrease the value of the option to smoke and was first interpreted as a kind of reappraisal. 22,47 Viewed from this perspective, the reduction in LPP amplitude during LATER vs. NOW could be interpreted such that smoking cues lose their appetitive qualities and, through this motivational shift, capture fewer attentional resources. However, Lopez et al, 22 recently proposed that focusing on the long-term (negative) consequences also actively shifts attention away from the cue, sharing this mechanism with distraction. According to this account, the reduction in LPP amplitude during LATER results from the fact that smokers do not engage with the cue and instead focus on mental imagery. Although this imagery is generally associated with smoking (e.g., lung cancer as a result of smoking), it is unrelated to the specific content of the cue (e.g., an ashtray, a cloud of smoke and a pack of cigarettes). Thus, whether NOW and LATER involve attention deployment as in DISTRACT or reappraisal of the value of the cue could depend on whether the specific picture content (e.g., ashtray) is part of the mental image of the (negative or positive) consequences of smoking. Future work could manipulate this aspect to further elucidate the processes involved in LATER and NOW.
Interestingly, the LPP during LATER was significantly higher than during DISTRACT, indicating a difference between the two strategies.
One explanation could be that the focus on long-term negative consequences induces negative emotions and arousal. 32 This notion would indicate that the value of the smoking option is decreased (as suggested by equally reduced craving scores), but LATER, as opposed to DISTRACT, imbues the cue with negative motivational significance. This interpretation would contradict the suggestion that LATER involves fully disengaging from the cue such that LPP amplitudes as a measure of motivated attention would remain elevated when compared with DISTRACT. Another explanation could be lower task engagement in the LATER strategy preventing LPP amplitudes to T A B L E 2 Results for planned post-hoc t-tests on LPP amplitudes. Regarding the re-exposure phase, pairing cues and the LATER instruction as few as three times during regulation appears sufficient to produce at least a small lasting association with negative consequences, suggesting that the value of the smoking option can be subject to change in the longer-term. 47,49 This confirms findings from an ER research that have found a lasting effect for reappraisal, 35 although there are also reports that have found no lasting effect. 15 In contrast, cues insufficiently processed because of prior distraction induced a degree of craving comparable to cues previously linked to the NOW instruction. This could explain why distraction is associated with higher risk of relapse 5 that individuals frequently engaging in distraction might repeatedly have to face high cue-induced craving because the cues are never subject to in-depth processing or reappraisal. It should be noted that LATER and DISTRACT did not differ in the degree to which craving increased from regulation to re-exposure.
This further emphasizes that the observed effect was small and that a difference score between phases may not be ideal to address lasting effects of ROC. Our behavioural results largely confirm ER results on re-exposure. 15,23 However, when comparing ROC and ER, differences should be considered. ER is often aimed at alleviating distress associated with negative emotions and therefore associated with a higher intrinsic motivation. In contrast, craving is associated with approach motivation and is usually alleviated by substance intake. This could pose a potential difficulty for successful ROC, in particular, achieving a lasting effect of ROC could require longer training than ER. Our findings may be relevant to future treatments, as they suggest that it may be more beneficial to focus on the negative consequences rather than distracting oneself, as this may reduce strong craving when encountering substance-related cues in the future.
However, we found no differences between the strategies regarding the LPP during re-exposure, suggesting that all smoking-related cues were similarly significant and captured higher attention than neutral pictures. This stands in line with previous results 23  passive viewing condition with all cues before the regulation phase could have provided a measure of baseline cue reactivity. This was not incorporated to prevent disengagement from the task and habituation. We included an active control condition with a focus on shortterm benefits of smoking instead of passive viewing to improve task compliance. This makes the comparison of the LPPs difficult because we cannot distinguish between habituation effects caused by processing of the picture and effects due to reappraisal of the meaning of a cue. The strategy instruction was presented briefly before the picture, potentially enabling participants to initiate the regulation before cue presentation, and it is possible that they did not include the cue in their imagination of short-or long-term consequences of smoking. It would also be interesting to see whether the effects of regulation and re-exposure would be greater if instructions were manipulated in a block-by-block rather than trial-by-trial fashion. Moreover, an important aspect could be to directly tie reappraisal to the content of the cue (e.g., 'this cigarette advertisement') instead of using a reappraisal of the general option to smoke ('smoking leads to cancer'). This could ensure that the content is fully processed and that the new meaning is actually linked to the cue.
In summary, this study examined lasting effects of cognitive regulation on craving and the LPP. The results provide evidence that reappraisal-related ROC and distraction achieve similar immediate effects. This study is the first to find evidence that reappraisal can have a lasting effect on cue-induced craving, whereas distraction does not. The implication for clinical practice is that distraction is efficient for short-term ROC, but that a reappraisal-related strategy is beneficial for sustained regulation.