Moderation of Nicotine Effects on Covert Orienting of Attention Tasks by Poor Placebo Performance and Cue Validity
Introduction and Rationale Given baseline-dependent effects of nicotine on other forms of attention, there is reason to believe that inconsistent findings for the effects of nicotine on attentional orienting may be partly due to individual differences in baseline (abstinence state) functioning. Individuals with low baseline attention may benefit more from nicotine replacement. Method The effects of nicotine as a function of baseline performance (bottom, middle, and top third of mean reaction times during placebo) were assessed in 52 habitual abstinent smokers (26 females/26 males) utilizing an arrow-cued covert orienting of attention task. Results Compared to a placebo patch, a 14 mg nicotine patch produced faster overall reaction times (RTs). In addition, individuals with slower RTs during the placebo condition benefitted more from nicotine on cued trials than did those who had shorter (faster) RTs during placebo. Nicotine also enhanced the validity effect (shorter RTs to validly vs. invalidly cued targets), but this nicotine benefit did not differ as a function of overall placebo-baseline performance. Conclusions These findings support the view that nicotine enhances cued spatial attentional orienting in individuals who have slower RTs during placebo (nicotine-free) conditions; however, baseline-dependent effects may not generalize to all aspects of spatial attention. These findings are consistent with findings indicating that nicotine\xe2\x80\x99s effects vary as a function of task parameters rather than simple RT speeding or cognitive enhancement.
1. Introduction<!>2.1. Participants<!>2.2. Design<!>2.2.1. Procedures<!>2.2.2. Orientation/practice sessions<!>2.2.3. Experimental sessions<!>2.2.4. Assessment of nicotine and smoking abstinence<!>2.3. Experimental Equipment, Software and Tasks<!>2.4. Analytic Procedures<!>3.1. Plasma Nicotine and Cotinine Concentrations Pre- and Post-Patch<!>3.2. Patch Blindness Assessment<!>3.3.1. Arrow-Cued Trials<!>3.3.2. No-cue trials<!>4. Discussion<!>4.1. Clinical Implications<!>4.2. Methodological Limitations and Future Directions<!>5. Conclusions<!>
<p>Nicotine and other cholinergic drugs can enhance a variety of attentional systems (see Levin and Simon 1998; Newhouse et al. 2004; Rezvani and Levin 2001 for reviews). For example, nicotine results in robust vigilance-enhancing and alerting effects (Gilbert et al. 2005). In a recent meta-analysis, Heishman et al. (2010) found significant beneficial effects of nicotine in both habitual smokers and nonsmokers on six components of cognitive functioning: fine motor, alerting attention-accuracy and response time (RT), orienting attention-RT, short-term episodic memory-accuracy, and working memory-RT, with effect sizes from 0.30 to 0.86. These findings support enhancement of cognitive functioning as a motive for smoking (Spielberger 1986).</p><p>However, there are less consistent findings of nicotine's effects on attentional orienting, the multi-stage process of selectively allocating attention to discrete areas of the visual field (Posner, 1980). Attentional orienting is a critical neurocognitive activity for attending to important environmental events during activities such as driving, monitoring children, or even playing sports. Covert orienting of attention tasks (COAT; Posner 1980) require participants to fixate centrally while covertly directing attention, without foveal eye movement, when cued laterally by a central arrow. Then, as quickly as possible, they respond to a peripheral target. On different trials, the central arrow either directs attention to the side at which the target subsequently appears (valid cue) or to the side opposite of the target (invalid cue). Reaction times (RTs) to targets are typically more rapid when preceded by valid relative to invalid cues (the validity effect), as attention has already been allocated to this target location. In contrast, RTs are typically slower in invalidly cued trials, where attention must be reoriented to unexpected target locations (Posner 1980; Petersen and Posner 2012).</p><p>The COAT has been used to characterize nicotine's enhancement of cued spatial attention (e.g., Thiel et al. 2005), which may have relevance to reinforcing effects of nicotine and motives for smoking. Research indicates that nicotine and cholinergic agonists can enhance visuospatial reorienting during the COAT and related tasks (Thiel et al. 2005; Thiel and Fink, 2008; Vossel et al. 2008). Such evidence points to nicotine speeding RTs for invalid cued targets and thereby reducing the validity effect, but other studies of the effects of nicotine on cued attentional orienting have been inconsistent.</p><p>One possible reason for inconsistent findings is that the effects of nicotine in nonsmokers may differ from the effects in smokers (Heishman et al 2002; Newhouse et al. 2004). In nonsmokers, Griesar et al. (2002) reported that transdermal nicotine, relative to placebo, reduced RTs to targets during a covert attention task, and nicotine was associated with a trend for increased validity effects; this validity effect improvement by nicotine only approached statistical significance, perhaps due to the small sample size (N= 12). Alternately, nicotine may have a general arousal effect, but no effect specifically associated with attentional orienting (Hahn et al. 2007). Other studies suggest that nicotine may have no effects on cued attentional orienting tasks in nonsmokers (Giessing et al. 2007) or that nicotine reduces reaction times (RTs) in both smokers and nonsmokers for invalid trials without influencing valid trials (Vossel et al. 2008; Witte et al. 1997).</p><p>The aforementioned inconsistent findings could also reflect that nicotine's effects on attentional reorienting relative to orienting depend upon the proportion of valid cues (e.g., 90% vs. 60% valid cues), as nicotine's effects on reorienting may not occur (and validity effects may actually improve with nicotine) under lower cueing reliability (i.e., 60%; Vossel et al. 2008).</p><p>Another important factor that may account for the inconsistent pattern of findings across studies is individual differences in baseline (nicotine-free) task performance. The present investigation examined the possibility that the effects of nicotine on visuospatial attention may depend, in part, on individual differences in baseline (placebo or abstinent state) attentional functioning. More specifically, individuals with poorer baseline attentional performance might differentially respond to nicotine versus those with better baseline performance. Perkins (1999) and Newhouse et al. (2004) review evidence supporting the view that poor baseline attentional/cognitive performance is associated with greater benefits from nicotine. Consistent with baseline-dependency, Patterson et al. (2010) recently found that poorer working memory on a rapid information processing task (the N-Back) during nicotine abstinence predicted more rapid resumption of smoking in individuals attempting smoking cessation. Baseline-dependent effects of nicotine have also been observed for P3 event-related potential amplitudes during involuntary novel auditory processing in nonsmokers, demonstrating increased attentional enhancement by nicotine only in individuals with relatively poor attentional capacity (Knott et al. 2014). We are not aware of studies assessing the influence of existing placebo-baseline deficits on covert spatial attention enhancement by nicotine in smokers.</p><p>Both theory and a large body of evidence also suggest that individual differences in neurobiological states and traits may mediate situational variability in the effects of nicotine on cognition and affect (Eysenck 1980; Gilbert et al. 1989; Perkins 1999). Eysenck (1980, 1997) proposed that nicotine's effects are moderated by pre-drug baseline brain activation that in turn is influenced by genetically influenced dispositional traits, situational arousal, and fatigue potential of the environment. It is therefore critical that the moderation of nicotine's effects by situational and individual difference factors be better characterized by systematic and well-controlled investigations, to investigate when and in whom nicotine influences visuospatial attention and to seek resolution of mixed findings. Current findings are from a larger study examining effects of nicotine replacement therapy (NRT), in the form of transdermal patches, and the moderation by DRD2 genotype, on selective attention and distraction. Specifically, in earlier reports, NRT was found to improve target detection accuracy and shorten RTs during rapid visual information processing (RVIP), depending on distractor visual field and DRD2 genotype (Gilbert et al. 2005). Also, DRD2 genotype and cue-target delays predicted differential nicotine benefit following emotionally positive and negative images (Hammersley et al. 2013).</p><p>The present study also examined gender because accumulating evidence suggests that NRT may be less effective in women and that women may be less sensitive to nicotine's reinforcing effects and more influenced by smoking cues (Perkins et al. 1999; Perkins 2001). More recent research also indicates that acute effects of nicotine may be differentially influenced by impulsivity-related factors (i.e., novelty seeking and disinhibition) in men versus women (Perkins et al. 2008), and that nicotine dose sensitivity can be influenced by whether a cognitive task tends to show sex-specific performance differences (i.e., gender-preferred tasks; Poltavski et al. 2012). However, gender differences in the effects of nicotine on visuospatial attention have not been characterized well in published studies. Nicotine patch may be an excellent manner to assess gender differences because the minimal sensory impact associated with this means of nicotine administration minimizes alternative explanations of these differences.</p><p>Primary aims of the present study were to assess cognitive/attentional individual differences in response to nicotine as a function of baseline performance levels during visual-spatial attention performance given previous theory (Eysenck, 1980; Perkins, 1999), and to further clarify inconsistent findings of the effects of nicotine on attentional orienting. Based on the above evidence, we expected that poorer placebo-baseline attention would predict greater effects of nicotine replacement therapy, and also that cue validity and gender would moderate nicotine's effects on COAT performance in overnight-deprived, moderately nicotine-dependent smokers.</p><!><p>The present study was approved by the Human Subjects Committee, the Institutional Review Board for the university, in accordance with ethical standards for human research. Participants used in the statistical analyses were 26 female and 26 male smokers with a mean age of 23.2 years (6.8 SD, 18–47 range) who smoked an average of 18.38 (5.4 SD, 10–40 range) cigarettes per day. Nicotine dependence was assessed with the Fagerström Test of Nicotine Dependence (FTND; Heatherton et al. 1991). The mean FTND score was 4.36 (1.5 SD, 1–8 range), indicating a moderate degree of dependence for the typical participant. Two males and two females were African Americans and the remaining participants were Caucasian.</p><p>Participants were recruited by newspaper ads and postings at the university and in the community. They were screened for both psychiatric and neurological history, by phone and during a face-to-face interviews, prior to consent for participation in the study. These interviews included screening for head injury history, current and former psychoactive drug or medication use, prescription and over-the-counter medications in the past two months, antihistamine use, allergies and possible allergic reactions, acute stressors, current and former psychological problems/diagnoses, prior exposure to nicotine patch, medical conditions in the past year, sleep patterns and duration, vision problems such as such as limited movement, limited vision, or lazy eye in either or both eyes or color blindness, and blood donation history. We further screened for medical conditions, including blood disorders, high blood pressure and heart disease, seizures or epilepsy, blood clotting disorders or deficiency, liver disease, bulimia or anorexia, and currently pregnant or trying to become pregnant. Exclusion criteria included smoking fewer than 10 cigarettes per day for the past year, habitual cigarette estimated nicotine deliveries of less than 0.6 mg, use of psychoactive drugs or medications other than caffeine, marijuana, and alcohol, excessive alcohol use (more than 28 drinks/week), age less than 18 or more than 48 years, non-English speaking, atypical sleep cycles, pregnancy, serious medical illness, and uncorrected visual problems. Age was restricted because of slower reaction times (Langan et al. 2010; Seidler et al. 2010) and poorer sight (Owsley 2011; Faubert 2002) with increasing age.</p><p>Participants were instructed not to smoke for the 12 hours preceding each of the experimental sessions and only those who adhered to this 12-hour abstinence were included in the data analysis. Adherence was checked prior to each session with expired breath carbon monoxide concentrations (see procedure section).</p><!><p>During each of the four experimental sessions participants completed the Posner (1980) covert orienting of attention task (COAT) twice. The study was double blind for the nicotine versus placebo status of the patches. The active vs. placebo patch order and task orders were counterbalanced across sessions in a within-participants design. Each participant randomly received a nicotine patch on one of the first two experimental sessions and a second nicotine patch during one of the last two experimental sessions. Two sessions on each of the two patch types were used to enhance reliability of findings and of individual differences in baseline (placebo condition performance), as well as to assess the reliability of baseline performance. A parent-study focus was on developing reliable individual-difference indices of the effects of nicotine; more testing sessions and two assessments within sessions were designed to help demonstrate reliability of individual differences.</p><!><p>Participants attended two orientation/practice sessions and four experimental sessions. Each participant sat alone in an experimental room that was electronically connected to a control room which also monitored behavior with video cameras. Participants earned $200 for completion of the study.</p><!><p>During the orientation sessions participants signed an informed consent document and then completed questionnaires and vision test and practiced experimental tasks. Participants were instructed not to consume alcohol or tobacco within 12 hours and to abstain from marijuana use within 72 hours before experimental sessions.</p><!><p>Sessions began between noon and 2:00 p.m. A minimum of 1 day and a maximum of 7 days separated each of the experimental sessions. Upon arrival at the laboratory, the participant's expired breath carbon monoxide (CO) concentration was monitored and blood samples were taken. Then a Nicoderm® 14 mg transdermal patch or placebo patch identical in appearance was placed on the upper arm two hours prior to the onset of the first experimental task. In order to minimize the ability of participants to differentiate active and placebo patches by itching or irritation, a cover bandage was used with capsaicin cream applied along the edges (See Gilbert et al. 2005). A 14 mg patch was used because in our pilot studies a significant proportion of smokers experienced lightheadedness, nausea, and/or sickness with 21 mg patches.</p><p>Participants then spent 2 hours completing questionnaires and reading other materials prior to beginning the experimental tasks. Reactions to the patch were monitored for checking relevant items (nausea, sickness, and dizziness) of the Feeling State Questionnaire (FSQ; Gilbert et al. 1992) every 15 minutes from baseline (pre-patch administration) through the start of the experimental session (2-hours post-patch administration). Craving was also assessed using FSQ to examine withdrawal alleviation and any associations of withdrawal alleviation with nicotine effects. The Patch Guess and Attribution Questionnaire (GAP; see Gilbert et al. 2005 for details) was completed at the conclusion of each experimental session to assess blindness to patch condition.</p><!><p>Overnight smoking abstinence and smoking status were verified using plasma nicotine concentration and from expired breath CO concentrations. Pre-session CO concentrations of 10+ ppm, more than 3 drinks of alcohol the evening before, fewer than 5 hours of sleep, illness, or other drug use, including marijuana, resulted in rescheduling of experimental sessions. Plasma nicotine concentrations of greater than 2.0 ng/ml resulted in elimination of the participant's data from analysis. Six individuals were eliminated from analysis for this reason. Details of these assessments are provided in Gilbert et al. (2005).</p><!><p>All tasks were presented using SuperLab™ 2.0 stimulus presentation software and response pads (Cedrus Corp, San Pedro, CA). Two covert attention tasks (Posner 1980) were performed: one at the onset and the other about 75 minutes later. Each covert attention task (COAT) consisted of 180 trials, with left and right arrow cues and no cues appearing on 60 trials each within a block. Of the 120 arrow-cue trials, 96 (80%) were valid trials and 24 (20%) were invalid trials. Half of the no-cue trials had a 100 ms interval before the occurrence of the target, and the other half had an 800 ms interval. These different delays prior to target presentation in the no-cue condition were used to prevent temporal anticipation patterns that would result from consistent intervals.</p><p>Each COAT trial consisted of the following sequence of events: a 1000 ms prompt to blink, a 500 ms central fixation cross, an 800 ms central arrow cue pointing left or right or absent (no arrow cue), a 100 ms asterisk target presented 5° to left or right of the fixation, and a 700 ms blank screen to reset the sequence (see Fig. 1). Different trial types were randomly mixed. Individuals were instructed to maintain fixation on the center of the screen and respond as rapidly as possible, without sacrificing accuracy, by pressing either the left or right key on a response box, indicating their detection of the left or right visual field location of the asterisk target. Time from presentation of the target to the button push response and response accuracy was recorded. Fixation crosses, arrow cues, and asterisk targets were white stimuli on a black background and subtended 1° of visual angle. Run time for this task was approximately 10 min.</p><!><p>COAT analyses were based on correct responses measured in mean RTs that occurred between 100 and 800 ms post-target presentation. Reaction times were aggregated across both COATs and are reported as sums of aggregate RTs for each condition. The total responses that were not analyzed due to errors (incorrect button presses) or discarded data outside of the 100 to 800 ms window were less than 4%, so no meaningful analysis of errors by condition was possible. Analysis of variance (ANOVA) probability values were based on Greenhouse-Geisser (1959) correction for sphericity of repeated measures. Non-corrected degrees of freedom are reported for purposes of clarity. The focused analysis approach recommended by Rosenthal et al. (2000) was used because of the specific hypotheses concerning the effects of nicotine. Thus, only nicotine main effects and predicted interactions involving nicotine are described. The ANOVAs also included Gender and an additional between-subjects factor with three levels — Placebo-RT — to which individuals were assigned based on their mean task performance RTs on the two placebo days (bottom, middle, and top thirds of mean placebo RT).</p><!><p>As detailed in Gilbert et al. (2005), plasma nicotine and cotinine concentrations were assessed from blood obtained immediately prior to the application of the patch and immediately after the completion of each session's final questionnaire. Mean cotinine concentration was calculated across experimental sessions and mean increase in nicotine blood plasma concentration was calculated for nicotine patch administrations. Mean pre-session plasma nicotine concentration was less than 1 ng/ml. Smoker status was verified by orientation session breath CO concentrations of greater than 15 ppm and by self-report. The nicotine patch resulted in an increase in plasma nicotine concentration of approximately 14.5 ng/ml, while there was no change in the placebo condition. Participant-reported abstinence time ranged from 12–16 hours. Overall RT effects benefit scores were calculated for improvements in RT on nicotine versus placebo patch. In bivariate correlations, mean plasma nicotine increase was not associated with overall RT benefit from nicotine, r = 0.123, p = .386, nor was mean baseline cotinine concentration, r = 0.043, p = .763. Using one-way Analysis of Variance (ANOVA) to assess group differences, there were no differences in total baseline cotinine concentration, F(2, 42) = 0.847, p = 0.436, or mean cotinine concentration, F (2, 51) = 1.71, p = .192, across the Placebo RT groups. Moreover, overall changes in nicotine blood levels from the nicotine patch did not vary by Placebo-RT groups for either cued trials, F(1, 48) = 2.3, p = .11, or no-cue trials, F(1, 48) = 1.73, p = .19.</p><!><p>On the Patch Guess and Attribution Questionnaire, the participants' mean certainty ratings of being on the nicotine patch were 57% for individuals on the nicotine patch and 49% for individuals on the placebo patch; certainty of receiving nicotine was significantly greater with the nicotine patch than with the placebo patch, F(1, 53) = 4.68, p < .05. Thus, about half of the individuals on the placebo patch believed with certainty that they were on the active patch, and more than 40% of those on the nicotine patch believed with certainty they were on the placebo patch, demonstrating that participants were close to chance levels statistically in guessing the patch that they had received and were therefore not very accurate. See Gilbert et al. 2005 for further details about assessment of patch blindness using this questionnaire.</p><!><p>To characterize the main effect and interactions involving Nicotine, the analysis of variance (ANOVA) was performed using the following within-subjects factors: Nicotine (nicotine vs. placebo) × Validity (valid vs. invalid cue) × Patch Exposure (first vs. second day of exposure to the nicotine and placebo patches) × Visual Field (left vs. right target location). Separate ANOVAs also included between-subjects factors Gender and Placebo-RT, to which individuals were assigned based on mean performance RTs on the two placebo days (bottom, middle, and top thirds of mean placebo RT). Participants were stratified into three separate Placebo-RT groups based on the sample size, and three separate groups are preferred to two because the inclusion of only two Placebo-RT groups would preclude identification of curvilinear effects.</p><p>As expected, nicotine was associated with shorter (quicker) RTs to all cued targets than placebo (542.08 vs. 576.37 ms), F(1,46) = 62.61, p < .001, partial eta2 = .55; however, these effects of nicotine were moderated by cue validity such that nicotine shortened RTs more in the valid than invalid condition (Fig. 2a and 2b), Nicotine × Validity, F(1,46) = 9.44, p = .003, partial eta2 = .156. The effects of nicotine were also moderated by Placebo-RT group, Nicotine × Placebo-RT, F(2,46) = 6.76, p = .003, partial eta2 = .216, such that longer RTs on placebo were associated with greater RT benefits (greater shortening of RTs on nicotine compared to placebo; See Fig. 3). Overall mean nicotine benefit, across Placebo Mean groups, demonstrates that the slowest individuals at placebo showed the greatest RT benefit from nicotine (Fig. 4), and planned pairwise comparisons showed that only the medium and slow groups at Placebo significantly improved RTs with nicotine (42.65 ms nicotine benefit in medium Placebo RT group; 45.64 ms nicotine benefit in slow Placebo-RT group), ps < .001. Group RTs were as follows for overall mean performance across cued trials: Fast Group mean RT = 486.20 (470.03–502.37 range), Medium Group mean RT = 546.24 (530.53–561.96 range), Slow Group mean RT = 644.66 (628.49–660.83 range).</p><p>Predicted gender differences in the main effects of nicotine on RTs were also not supported, F(1, 50) = 0.006, p = .938, partial eta2 = .00. Separate analyses of covariance (ANCOVAs) were conducted, using FTND dependence scores, age and cotinine levels on placebo days as covariates. FTND, age, and placebo cotinine covariates did not interact with any of the above reported main effects and interactions. Craving change scores on the Feeling State Questionnaire (FSQ) from baseline to patch administration on nicotine versus placebo were also entered as covariates in ANCOVA and did not interact with reported main effects and interactions. There were also no significant differences between genders or Placebo-RT groups on either overnight craving scores or craving change scores.</p><p>Performance was highly consistent across both placebo days, r = 0.76, p < .001 and across both nicotine days, r = 0.86, p < .001. The total group ranking generated by the average rank across the two placebo conditions was also highly consistent with both the first, rs = 0.85, p < .001, and second, rs = 0.91, p < .001, placebo task performances, demonstrating stability of the group rankings.</p><!><p>The main analysis of variance was performed on no-cue trials using the following within-subjects factors in the no-cue COAT trials: Nicotine (nicotine vs. placebo) × Target Delay (100 vs. 800 ms delay) × Patch Exposure (first vs. second day of exposure to the nicotine and placebo patches) × Visual Field (left vs. right target location). Separate ANOVAs also included between subjects factors Gender and Placebo-RT, to which individuals were assigned, based on mean placebo performance during no-cue trials (bottom, middle, and top thirds of mean placebo RT). Again, participants were stratified into three separate Placebo-RT groups based on the sample size, and in order to identify possible curvilinear effects. As described below, as predicted the ANOVA for no-cue trials revealed significant main effects for Nicotine, but only a trend toward significance for the expected Nicotine × Placebo-RT Group interaction.</p><p>As expected, nicotine was associated with faster overall reaction times (RTs) to no-cue targets, F(1,46) = 51.22, p < .001, partial eta2 = .501. The predicted RT-reducing effects of nicotine being greatest in individuals who performed more poorly during placebo conditions only approached significance, Nicotine × Placebo-RT Group, F(2,46) = 3.12, p = .053, partial eta2 = .113. Group RTs were as follows for overall mean performance across cued trials: Fast Group mean RT = 533.60 (512.56–554.63 range), Medium Group mean RT = 584.60 (564.80–604.39 range), Slow Group mean RT = 694.29 (674.11–714.47 range).</p><p>Males compared to females showed greater RT-speeding effects of nicotine on the second exposure to nicotine, Nicotine × Exposure × Gender, F(1,46) = 9.58, p = .003, partial eta2 = .172 (Nicotine benefit on exposure-2 for males: 50.77 ms vs. Nicotine benefit on exposure-2 for females: 30.94 ms).</p><p>Finally, both baseline (placebo) performance, r = 0.81, p < .001, and nicotine performance, r = 0.86, p < .001, were highly consistent across both days. Further demonstrating stability of the group rankings, the total group ranking generated by the average rank across the two placebo conditions was highly consistent with both the first, rs = 0.88, p < .001, and second, rs = 0.83, p < .001, placebo task performances.</p><!><p>The present study assessed the influence of nicotine replacement therapy (NRT) patches on spatial attention in overnight-deprived, habitual and dependent smokers. Importantly, the observed effects of nicotine may reflect nicotine withdrawal alleviation, though we refer to nicotine effects for simplicity. Nicotine effects on cued trials were moderated by individual differences in placebo-baseline performance; specifically, NRT enhanced general visuospatial attention performance by reducing RTs to a greater extent in individuals with poorer placebo-baseline performance than in those with better performance. Nicotine effects were also moderated by cue validity, in that nicotine had greater RT-reducing effects for valid than for invalid trials.</p><p>Contrary to expectations, the hypothesis that the RT-reducing effects of nicotine would vary by gender was not supported. However, there was some evidence that the effects of nicotine and gender were dependent upon the repeated exposure to nicotine or to experimental settings, with performance by males on no-cue trials particularly enhanced by nicotine on the second nicotine administration in comparison to females possibly due to either lowered situational arousal potential or habituation to the experimental settings and greater fatigue and boredom after repeated testing. Previous work has demonstrated that nicotine enhances interest in demanding and potentially boredom-inducing tasks (Volkow et al. 2004), and that NRT may be less effective for women (Perkins 2001), though there are relatively few studies examining possible gender differences in the effects of NRT on spatial attention or in habituation to nicotine. As there were minimal effects of repeated exposure, and this was not a major focus of the current study, this finding is not further discussed in great detail.</p><p>The findings of greater benefits of NRT on cued trials in individuals with poorer baseline performance (placebo-RT) support the notion that individuals with attentional difficulties may use nicotine as a form of self-medication for such neurocognitive deficits (Perkins 1999; Newhouse et al. 2004). However, it is not clear whether these differences in attentional performance reflect basic, possibly genetically influenced effects, effects of chronic smoking, and/or random variations in performance. The placebo-baseline dependent individual differences observed in the present sample may have partly reflected habitual smoking differences, though FTND nicotine dependence did not correlate with baseline performance or baseline cotinine concentration in our study.</p><p>However, baseline-dependent effects of nicotine patch in nonsmokers (Wachter & Gilbert, 2013) are consistent with the view that there may be inherent self-medication effects of nicotine for low placebo-performance individuals. FTND, cotinine, or age covariates did not interact with reported main effects and interactions. Thus, habitual smoking level does not appear responsible for the observed effects. Baseline performance was assessed on two placebo days and the correlations for performance between both placebo days and nicotine days were high. Thus, regression towards one's personal mean also seems to be an unlikely cause of the observed baseline-dependent effects.</p><p>Although individual differences in heart rate-assessed bioavailability/concentration of nicotine have been examined and found to relate to neural indices of cued visual-spatial attention (Shah et al. 2011; Impey et al. 2013), we assessed individual differences in actual bioavailability (increase in nicotine blood concentration) and found that changes in blood nicotine concentration did not vary by Placebo-RT groups. Although nicotine blood concentration does not directly assess nicotine brain concentrations or receptor binding, there is evidence that blood concentrations of nicotine are associated with brain concentrations (Rose et al. 2010). Therefore, individual differences in nicotine absorption also do not appear responsible for observed findings.</p><p>Previous research has noted baseline-dependent effects of nicotine (Perkins 1999; Wachter and Gilbert, 2013). Rate dependency is seen with nicotine and other stimulants that can increase low baseline rates and decrease high baseline rates of performance (McMillan and Leander, 1976). Other research suggests that poorer attentional performance at placebo or baseline is associated with greater nicotine benefit (Baschnagel and Hawk 2008; Newhouse et al. 2004). Recent evidence also indicates that transdermal nicotine can increase sustained attention in adult nonsmokers with poorer attentiveness, but negatively impacts participants higher in attentiveness (Poltavski and Petros, 2006). In nonsmokers, findings by Knott et al. (2014) generally support baseline-dependent nicotine effects on both voluntary and involuntary neural aspects of attention as measured by ERPs. Such findings in nonsmokers suggest baseline-dependent nicotine effects separate from mere withdrawal alleviation, in support of Perkins' (1999) model.</p><p>Further support for baseline-dependency of nicotine effects is seen on tasks assessing executive functioning, such as antisaccade performance (Petrovsky et al. 2012; Wachter and Gilbert 2012). The present study used a version of the covert attention task (COAT) with central arrow cues, requiring some reliance on executive functions (Posner 1980), perhaps explaining the observed effects. Other studies have also shown that nicotine's influence on covert attention may be dependent upon top down information about predictive cueing (Meinke et al. 2006), and nicotine may exert other important effects on executive functions (Heishman et al. 2010). Observed baseline-placebo dependency of nicotine effects may therefore be most apparent on tasks involving executive functioning, and perhaps partly explains why only a trend toward significance was seen in the present study for baseline-placebo dependent effects of nicotine during no-cue trials on the COAT.</p><p>Findings on the enhancement of the validity effect by nicotine in the present study, with greater nicotine effects for valid (correctly cued) than invalid cued (reorienting) conditions, matches previous research by Griesar et al. (2002), who found similar though not statistically significant effects of nicotine on the validity effect in 12 nonsmokers. Kleykamp et al. (2005) found no effects of nicotine on attentional alerting, orienting or executive functioning in 20 nonsmokers. The small sample sizes in these two previous studies may explain their lack of significant findings. However, other research examining cued spatial attention in nonsmokers has found that nicotine gum speeded reaction times specifically for invalid trials, while alerting was not influenced (Thiel et al. 2005). It has also been demonstrated, both behaviorally and neurally, that nicotine differentially modulates reorienting in high but not low cue validity conditions (Vossel et al. 2008).</p><p>Hence, such findings further support nicotine's role in decreasing utilization of spatial cues during high cue validity by reducing top-down information processing (Thiel and Fink 2008; Yu and Dayan 2005) but some methodological differences among the above studies and the present study may preclude direct comparisons. Significant validity effect enhancement in the present study may reflect our larger sample size and/or a sample of smokers rather than nonsmokers. It is possible that transdermal patches affect attentional orienting differently than other NRTs. The present study also used 80% valid cues, which may not have been a sufficiently high validity condition for nicotine to differentially speed responses to invalid cued targets and reduce the validity effect through decreased top-down processing.</p><!><p>Possible clinical implications of the present findings include that individuals who receive greater cognitive enhancement from nicotine use are more likely to continue smoking or using other forms of tobacco, and may be at risk for relapse following smoking cessation due to poor attention (e.g., Gilbert, 1995; Patterson et al. 2010). Attentional deficits might maintain smoking behavior in smokers who are not motivated to quit smoking, or may reinforce initial nicotine use, suggesting potential avenues for smoking cessation interventions. Findings from our studies and others also appear consistent with self-medication in smokers (Eysenck 1997; Perkins 1999) and may suggest possible utilization of cholinergic agonists for clinical disorders involving disrupted attention (Heishman et al. 2010; Poltavski and Petros, 2006; Levin et al. 2006). Learning which components of attention are improved by NRT is an important step.</p><!><p>Limitations of the present study include a relatively modest sample size not fully representative of smokers, particularly with respect to age, length of smoking history, and race. Effects of NRT in very light, heavier, older, non- and ex-smokers, and substance abusing smokers were not assessed. It cannot be determined from the present findings whether observed effects reflect amelioration of nicotine withdrawal or inherent benefit of nicotine, though Heishman et al.'s (2010) meta-analysis suggests similar attentional effects in smokers and nonsmokers, separate from withdrawal alleviation. Moreover, our findings that changes in craving were not associated with reported effects further supports this assertion.</p><p>Furthermore, our findings are limited by the use of only one dose of nicotine delivered by transdermal patch. Effects produced by other means of nicotine administration, different doses of nicotine, and different degrees of nicotine deprivation should be systematically examined. Another current limitation is that RT speeding may indicate motor speed rather than attentional improvement (Baschnagel and Hawk, 2008), as nicotine may impact cognitive performance differently when measured with accuracy tasks (Vangkilde et al. 2011); in the COAT paradigm used at present, target accuracy was too high to assess enhancement by nicotine. Finally, to better characterize baseline-dependent nicotine effects, self-reported attention problems or distinct baseline performance sessions, rather than placebo condition, could be assessed.</p><!><p>Despite limitations, the present study produced important findings in which some support was provided for baseline-dependency of nicotine's attentional effects. Whether due to inherent nicotine effects or withdrawal amelioration, nicotine was differentially beneficial to those with lower baseline spatial attention performance. The current findings extend evidence for baseline-dependent effects to cued spatial attention and baseline dependency to placebo/nicotine-free conditions. Confidence in the validity of the placebo baseline-dependent effects of nicotine in the present study is strengthened by our use of two baseline conditions and the demonstration of their reliability. Further research examining individual differences underlying effects of nicotine on attention is needed.</p><!><p>This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.</p><p>The authors have no conflicts of interest with the submitted work.</p>