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Effects of Nicotine on Inhibitory Control in Humans
C H A P T E R
19 Effects of Nicotine on Inhibitory Control in Humans Ulrich Ettinger*, Veena Kumari† †
*Department of Psychology, University of Bonn, Bonn, Germany Centre for Cognitive Neuroscience, Division of Psychology, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
Abbreviations ADHD ANT mg RT SSRT
attention deficit hyperactivity disorder attention network test milligram reaction time stop signal reaction time
19.1 INTRODUCTION The ability to inhibit unwanted actions, thoughts, or emotions is an important function serving goal-directed behavior. Inhibiting impulses and inappropriate (re) actions is frequently required in everyday life, and the ability to do so is related to advantageous individual and societal functioning. Accordingly, enhancing the ability to inhibit unwanted behaviors has been in the focus of several streams of research. While some researchers have aimed to improve inhibitory control via training, another widely adopted approach is the application of cognition-enhancing substances such as the nicotinic acetylcholine receptor agonist nicotine. The study of pharmacological influences on inhibitory control is important for a number of reasons. First, such work has the potential to identify domains of cognition that can be enhanced in healthy humans to improve function in occupational, educational, and other societal contexts. Second, inhibitory impairments are observed in some psychiatric and neurological patient groups. Developing treatments to alleviate these deficits is an unmet clinical need. Third, regarding nicotine, it is important to understand the factors that cause and maintain cigarette smoking. These may include beneficial effects on aspects of cognition. Finally, the experimental study of
Neuroscience of Nicotine https://doi.org/10.1016/B978-0-12-813035-3.00019-8
drug effects on inhibitory control may inform models of cognition and brain function. This chapter focuses on nicotine effects on inhibitory control. Inhibitory control includes both the inhibition of a motor response and the attentional control of interference from distracting information. The chapter discusses nicotine effects on the most widely studied inhibitory paradigms, namely, the antisaccade, stop-signal, go/no-go, Stroop, and flanker tasks. Given the considerable methodological heterogeneity in this literature, findings from controlled nicotine applications (e.g., patch, tablet, injection, or gum) and cigarette smoking in deprived smokers are discussed. For reasons of space, only human studies are considered.
19.2 EFFECTS OF NICOTINE ON RESPONSE INHIBITION AND INTERFERENCE CONTROL 19.2.1 Antisaccade Tasks In the antisaccade task (Fig. 19.1), participants are instructed to make a rapid eye movement, a saccade, away from a sudden-onset peripheral target while avoiding a saccade toward it. The primary measure of inhibitory control on this task is the direction error rate, that is, percentage of trials on which the participant first looked toward the peripheral target. Additionally, latencies (RTs) of correct responses are often reported. Prosaccades are typically included as sensorimotor control condition. Numerous studies have provided evidence of beneficial effects of nicotine on antisaccade task performance.
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FIG. 19.1 Flowchart of an antisaccade task. In the antisaccade task, a rapid eye movement has to be made in the opposite direction of a peripheral stimulus (indicated here by a gray arrow). Antisaccade trials may be presented blocked, as in this example, or interleaved with prosaccade trials (saccades toward the target).
These effects have been reported with study designs differing considerably with regard to task characteristics (e.g., blocked or mixed antisaccade/prosaccade tasks), method of nicotine application (e.g., cigarette smoking after withdrawal, gum, nasal spray, injection, and patch), clinical characteristics (e.g., schizophrenia patients, schizotypal individuals, and controls), and smoking status (e.g., smoker and nonsmoker). Reductions in direction errors with nicotine have been observed in most (Dawkins, Powell, Pickering, Powell, & West, 2009; Dawkins, Powell, West, Powell, & Pickering, 2007; Depatie et al., 2002; Larrison, Briand, & Sereno, 2004; Larrison-Faucher, Matorin, & Sereno, 2004; Petrovsky et al., 2012, 2013; Pettiford et al., 2007; Powell, Dawkins, & Davis, 2002; Rycroft, Hutton, & Rusted, 2006; Schmechtig et al., 2013), but not all, studies (Ettinger et al., 2009, 2017; Rycroft et al., 2007; Thaker, Ellsberry, Moran, Lahti, & Tamminga, 1991; Wachter & Gilbert, 2013). Nicotine may also reduce antisaccade latencies (Bowling & Donnelly, 2010; Ettinger et al., 2009; Larrison et al., 2004; Larrison-Faucher et al., 2004; Petrovsky et al., 2013; Rycroft et al., 2006, 2007; Wachter & Gilbert, 2013), although not all studies have observed this effect (Depatie et al., 2002; Ettinger et al., 2017; Petrovsky et al., 2012; Schmechtig et al., 2013; Thaker et al., 1991). It should be noted that not all studies have reported latencies. While these effects are generally independent of clinical (schizophrenia, schizotypy, and control) and smoking (smoker and nonsmoker) status, there may be effects of baseline dependency with regard to antisaccade
performance (however, see Ettinger et al., 2017). For example, a study of schizophrenia patients showed greater improvement in low-performing patients (LarrisonFaucher et al., 2004). Additionally, Petrovsky et al. (2012) reported that nicotine reduced antisaccade errors in lowperforming but not in high-performing healthy participants, without affecting antisaccade latencies or prosaccade performance. Baseline dependency was also observed by Wachter and Gilbert (2013), who reported lower antisaccade but not prosaccade latency following a nicotine patch in poor and average (but not high) performing smokers, without any effects on error rates. To conclude, nicotine has beneficial effects on either direction errors or antisaccade latencies in the majority of studies. Given that most studies report no significant effects on performance on the prosaccade control task (Dawkins et al., 2007; Depatie et al., 2002; Ettinger et al., 2009; Larrison et al., 2004; Larrison-Faucher et al., 2004; Petrovsky et al., 2012; Pettiford et al., 2007; Schmechtig et al., 2013; Thaker et al., 1991; Wachter & Gilbert, 2013; however, see Ettinger et al., 2017; Petrovsky et al., 2013), these findings may reflect beneficial effects on the topdown control of saccadic eye movements.
19.2.2 Stop-Signal Tasks The stop-signal task (Fig. 19.2) is a measure of stopping or canceling a motor response. The task has been widely used to model the cognitive and neural mechanisms of
FIG. 19.2 Flowchart of a stop-signal task. In the stop-signal task, a response in a choice reaction task has to be stopped when a sudden-onset stop signal occurs. Here, the participant has to respond by indicating the direction of the target arrow (left or right) but has to stop this response when shortly after the target a stop signal (here, an arrow pointing up) is shown. The stop signal may also be an auditory stimulus.
19.2 EFFECTS OF NICOTINE ON RESPONSE INHIBITION AND INTERFERENCE CONTROL
response inhibition as well as deficits in inhibitory control in psychiatric and neurological patients. The key dependent variable is the SSRT, an indirect measure of the speed of the stopping process, but go RTs and percentages of correct responses are also reported in some studies. Beneficial effects of nicotine on SSRT have been observed in nonsmoking adolescents (Potter & Newhouse, 2004) and adults (Potter & Newhouse, 2008) with attention deficit hyperactivity disorder (ADHD); in nonsmoking young adults with high levels of impulsivity (Potter, Bucci, & Newhouse, 2012); and, weakly, in healthy nonsmokers (Logemann, B€ ocker, Deschamps, Kemner, & Kenemans, 2014b). Other studies, however, have failed to observe effects in healthy nonsmokers (Ettinger et al., 2017; Wignall & De Wit, 2011), smokers, (Bekker, B€ ocker, Van Hunsel, van den Berg, & Kenemans, 2005) or a combined sample of smokers and nonsmokers (Logemann, B€ ocker, Deschamps, Kemner, & Kenemans, 2014a). More consistent evidence of beneficial effects of nicotine on SSRT, however, comes from studies of smokers in a state of abstinence. Better performance following smoking as usual compared to abstinence was reported in most studies (Ashare & Hawk, 2012; Charles-Walsh, Furlong, Munro, & Hester, 2014; Tsaur, Strasser, Souprountchouk, Evans, & Ashare, 2015), although one study showed an increase in SSRT following smoking in smokers, suggesting disinhibition with nicotine (Austin, Duka, Rusted, & Jackson, 2014). Overall, it appears that nicotine improves stop-signal task performance in individuals with inhibitory impairments, that is, patients with ADHD and cigarettewithdrawn smokers. The experimentally controlled application of nicotine to healthy smokers and nonsmokers does not, however, appear to reliably enhance performance on this task.
19.2.3 Go/No-Go Tasks Go/no-go tasks (Fig. 19.3) are widely used to assess the ability to inhibit a dominant motor response. The most common measure of inhibitory control on the task is the (commission) error rate, that is, the percentage of responses on no-go trials, although studies have frequently also reported the RT of responses on go trials. While there is evidence of beneficial effects of cigarette smoking on no-go errors in smokers (Kozink, Kollins, & McClernon, 2010), most studies appear not to find significant effects of nicotine, including designs using cigarettedeprived smokers (Ettinger et al., 2017; Evans, Park, Maxfield, & Drobes, 2009; Giessing, Thiel, AlexanderBloch, Patel, & Bullmore, 2013; Harrison, Coppola, & McKee, 2009; Smucny, Olincy, Eichman, & Tregellas, 2015). One study of smokers with ADHD and smoking
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FIG. 19.3 Flowchart of a go/no-go task. In go/no-go tasks, the participant has to respond to a frequent go stimulus (here, a black circle) but withhold the response when a no-go stimulus is shown (here, a blue circle). In variants of the task, oddball stimuli are included. These also differ from the go stimulus in one stimulus dimension (e.g., color; an oddball stimulus in this example may thus be a green circle [not shown]) but have to be responded to like go stimuli.
controls observed that the patients made more commission errors when abstinent compared to a satiated state and more errors than the control group when abstinent (McClernon et al., 2008). There is also evidence of shorter (Giessing et al., 2013; Harrison et al., 2009; Houlihan, Pritchard, Krieble, Robinson, & Duke, 1996) and less variable (Houlihan et al., 1996) RTs on go trials with nicotine in nicotinedeprived smokers (however, see Ettinger et al., 2017; Kozink et al., 2010; Smucny et al., 2015). To conclude, the majority of studies have failed to provide evidence of beneficial nicotine effects on response inhibition in go/no-go tasks, and evidence is mixed with regard to effects on go RTs.
19.2.4 Stroop Tasks In the Stroop task (Fig. 19.4), the prepotent tendency to name a color word has to be inhibited; instead, the nondominant response of naming the print color of the word has to be performed. The Stroop task and its variants are widely applied in cognitive neuroscience, psychopharmacology, and psychopathology research. The key performance measure is the Stroop effect, that is, the difference in RTs or error rates between incongruent and congruent conditions.
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Woodward, 1991; Wesnes & Warburton, 1978; Wignall & De Wit, 2011) and patients with ADHD (Potter & Newhouse, 2004) and schizophrenia (Barr et al., 2008). There is also evidence that nicotine effects on Stroop performance may depend on CHRNA5 genotype ( Jensen et al., 2015) and smoker status, with beneficial effects observed in smokers but not in nonsmokers (Grundey et al., 2015). Overall, therefore, nicotine effects on inhibitory control in the Stroop task appear not to be reliable. The reasons for this are not clear, as both positive and negative effects have been obtained across smoker and nonsmoker samples as well as application methods (e.g., cigarettes in smokers vs controlled application of patches).
19.2.5 Flanker Tasks FIG. 19.4 Flowchart of a Stroop task. In the Stroop task, the participant is required to name the color that the word stimulus is printed in. The flowchart shows a randomized sequence of incongruent and congruent stimuli. Stimuli may also be presented blocked, that is, in separate lists of congruent and incongruent stimuli. Stroop tasks often also include a color bar condition to measure simple color naming time and frequently employ a central fixation cross before stimulus onset (not shown here).
A large number of studies have examined the influence of nicotine on the Stroop effect. Studies have employed both experimentally controlled applications and naturalistic methods involving cigarette smoking in smokers after variable durations of deprivation. Overall, the majority of studies have failed to observe beneficial influences of smoking or controlled applications of nicotine on the size of the Stroop effect (Cook, Gerkovich, Graham, Hoffman, & Peterson, 2003; Della Casa, H€ ofer, Weiner, & Feldon, 1999; Ettinger et al., 2017; Evins et al., 2005; Foulds et al., 1996; George et al., 2002; Ilan & Polich, 2001; Kos, Hasenfratz, & B€ attig, 1997; Levin et al., 1996; Mancuso, Warburton, Melen, Sherwood, & Tirelli, 1999; Parrott & Craig, 1992; Poltavski & Petros, 2006; Rusted, Caulfield, King, & Goode, 2000; Suter, Buzzi, Woodson, & B€ attig, 1983; Tsaur et al., 2015; Wesnes & Revell, 1984; Xu et al., 2007; Xu & Domino, 2000; Zack, Belsito, Scher, Eissenberg, & Corrigall, 2001). Other studies, however, have reported general enhancement of task performance (Atzori, Lemmonds, Kotler, Durcan, & Boyle, 2008; Azizian et al., 2010; Mancuso et al., 1999; Pomerleau, Teuscher, Goeters, & Pomerleau, 1994; Potter & Newhouse, 2008; Rusted et al., 2000; Zack et al., 2001). Yet, other studies have observed selective improvements in the Stroop effect in healthy individuals (Domier et al., 2007; Hasenfratz & B€ attig, 1992; Landers, Crews, Boutcher, Skinner, & Gustafsen, 1992; Provost &
Flanker tasks (Fig. 19.5) are popular measures of attentional interference. In flanker tasks, a response to a central stimulus is required, whereas peripheral flankers are to be ignored. The flanker effect describes the decrement in performance when peripheral flankers are incongruent with the central stimulus, compared to congruent or neutral conditions. A variant of the flanker task is the attention network test (ANT), which in addition to the conflict
FIG. 19.5 Flowchart of a flanker task. In this variant of the flanker task, the participant is required to indicate with a button press the direction of the central arrow (right or left) while ignoring the flanking distractors. This flowchart shows a randomized sequence of congruent and incongruent trials. Trials may also include neutral flankers and frequently employ a central fixation cross before stimulus onset (not shown here).
MINI-DICTIONARY OF TERMS
effect due to incongruent flankers taps alerting and orienting aspects of attention. While one study observed more efficient interference control on the ANT following a 21 mg nicotine patch in smokers with schizophrenia and smoking controls (AhnAllen, Nestor, Shenton, McCarley, & Niznikiewicz, 2008), other studies have failed to observe nicotine effects on flanker interference control in snuff users (Lindgren, Stenberg, & Rosen, 1996), nonsmokers (Ettinger et al., 2017; Kleykamp, Jennings, Blank, & Eissenberg, 2005; Wignall & De Wit, 2011), or samples of smokers and nonsmokers (Myers, Taylor, Salmeron, Waters, & Heishman, 2013). The study by Lindgren and colleagues, however, reported an overall reduction in RT and improvement in correct response rate following oral snuff, suggesting general performance-enhancing effects of nicotine (Lindgren et al., 1996). Flanker tasks have also been applied to investigate nicotine effects in smokers abstinent from smoking. One study observed that smokers had generally (irrespective of flanker congruency) higher RTs after overnight abstinence compared to ad lib smoking (Schlienz, Hawk, & Rosch, 2013). In another study, smokers showed reduced speeded accuracy during abstinence compared to smoking as usual (Schlienz & Hawk, 2017). Overall, therefore, effects of nicotine administration on interference control on flanker tasks are likely to be small, with most studies failing to report interference-specific effects or any effects at all.
19.3 CONCLUSIONS Overall, while there is evidence of beneficial effects of nicotine on inhibitory control, the literature is rather mixed. The most consistent effects are observed with the antisaccade task, where most studies report improvements in error rate and/or latency. The majority of studies also report beneficial effects on the SSRT, especially in impaired populations. The weight of evidence points against consistently positive effects on go/no-go, Stroop, and flanker tasks. These findings may be reconciled with earlier conclusions that nicotine improves more basic functions of attention, such as alertness and orienting, more strongly than the selectivity function of attention (Heishman, Kleykamp, & Singleton, 2010; Provost & Woodward, 1991). It should be noted, however, that improvements in basic, bottom-up attentional processing with nicotine may conceivably result in impaired top-down control (Ettinger et al., 2017; Rycroft et al., 2006), a pattern that is rarely observed. This suggests that nicotine may have positive effects on components of information processing that not only benefit basic attentional functions but also may be drawn upon in top-down control processes.
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The reasons for inconsistent effects on go/no-go, Stroop, and flanker tasks are unclear but may involve task factors, participant factors, and drug dose factors as well as their interactions. Task factors, such as inhibitory load, attentional load, or general task complexity, may contribute to variable nicotine effects across tasks. It is intriguing that effects appear to be more consistent on antisaccade and stopsignal tasks than on other tasks. This issue has not been systematically investigated. Designs that selectively vary relevant task features and inhibitory requirements are needed. Participant factors were found to play a role on antisaccade, stop-signal, and Stroop tasks in some studies. These factors include baseline performance (antisaccades), clinical conditions and/or level of impulsivity (stop-signal and go/no-go), genotype (Stroop), and smoking status (Stroop). These factors likely play an important role in explaining interindividual differences in nicotine response and interstudy differences in overall results (given differences in participant recruitment and selection between studies). Finally, dose dependency of nicotine effects on inhibition has been observed in some (Larrison-Faucher et al., 2004; Poltavski, Petros, & Holm, 2012) but not in other studies (Bekker et al., 2005; Foulds et al., 1996; Kleykamp et al., 2005; Meyers et al., 2015; Parrott & Craig, 1992). A related issue is that certain methods of nicotine administration allow a better titration than others (e.g., injection vs smoking) to achieve optimal dosages to meet individual participants’ needs. Generally, however, the issue of dose dependency merits further attention. Additionally, dose dependency may interact with participant and task factors.
MINI-DICTIONARY OF TERMS Antisaccade A saccade made in opposite direction to a sudden-onset, peripheral stimulus. Commission error A response to a stimulus that should not have been responded to. Flanker effect The difference in RT between incongruent and congruent conditions in flanker tasks. Reaction time (RT) The time, typically given in milliseconds, from stimulus appearance until the participant’s behavioral response. Saccade A rapid, conjugate movement of the eyes. Stop-signal reaction time (SSRT) The latency of the stopping process in the stop-signal task. The SSRT cannot be directly observed but is estimated. Stroop effect The interference of the meaning of a color word with the response to its print color. Naming the color in which a color word is printed is faster and less error-prone when the print color corresponds to the word (e.g., the word BLUE printed in blue) than when print color and word do not correspond (e.g., the word YELLOW printed in green).
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Key Facts of Inhibitory Control • The term inhibition denotes a heterogeneous construct that comprises a number of different phenomena in neuroscience and psychology. • In cognitive psychology, inhibitory control is a key executive function that refers to the ability to suppress actions, thoughts, and emotions. • Having to inhibit unwanted reactions, impulses, or emotions features prominently in everyday life. • Deficits in inhibitory control are observed in numerous neurological and psychiatric conditions. • Inhibitory control generally shows good temporal stability and significant heritability. • The neural networks underlying inhibitory control include the prefrontal cortex and its posterior cortical and subcortical projection targets. Summary Points • This chapter reviews the literature on nicotine effects on inhibitory control in humans. • The included inhibitory control paradigms are the antisaccade, stop-signal, go/no-go, Stroop, and flanker tasks. • Studies of both controlled applications (e.g., patch, tablet, injection, lozenge, spray, or gum) and cigarette smoking in deprived smokers are included. • The majority of studies of antisaccade tasks observed beneficial effects. • Beneficial effects on stop-signal tasks are observed in populations with inhibitory impairment. • Effects on go/no-go, Stroop, and flanker tasks are less consistent. • Overall, the literature suggests that nicotine effects on inhibitory control may be subtle, with task, participant, and dosage factors likely playing a role.
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19 Effects of Nicotine on Inhibitory Control in Humans Ulrich Ettinger*, Veena Kumari† †
*Department of Psychology, University of Bonn, Bonn, Germany Centre for Cognitive Neuroscience, Division of Psychology, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
Abbreviations ADHD ANT mg RT SSRT
attention deficit hyperactivity disorder attention network test milligram reaction time stop signal reaction time
19.1 INTRODUCTION The ability to inhibit unwanted actions, thoughts, or emotions is an important function serving goal-directed behavior. Inhibiting impulses and inappropriate (re) actions is frequently required in everyday life, and the ability to do so is related to advantageous individual and societal functioning. Accordingly, enhancing the ability to inhibit unwanted behaviors has been in the focus of several streams of research. While some researchers have aimed to improve inhibitory control via training, another widely adopted approach is the application of cognition-enhancing substances such as the nicotinic acetylcholine receptor agonist nicotine. The study of pharmacological influences on inhibitory control is important for a number of reasons. First, such work has the potential to identify domains of cognition that can be enhanced in healthy humans to improve function in occupational, educational, and other societal contexts. Second, inhibitory impairments are observed in some psychiatric and neurological patient groups. Developing treatments to alleviate these deficits is an unmet clinical need. Third, regarding nicotine, it is important to understand the factors that cause and maintain cigarette smoking. These may include beneficial effects on aspects of cognition. Finally, the experimental study of
Neuroscience of Nicotine https://doi.org/10.1016/B978-0-12-813035-3.00019-8
drug effects on inhibitory control may inform models of cognition and brain function. This chapter focuses on nicotine effects on inhibitory control. Inhibitory control includes both the inhibition of a motor response and the attentional control of interference from distracting information. The chapter discusses nicotine effects on the most widely studied inhibitory paradigms, namely, the antisaccade, stop-signal, go/no-go, Stroop, and flanker tasks. Given the considerable methodological heterogeneity in this literature, findings from controlled nicotine applications (e.g., patch, tablet, injection, or gum) and cigarette smoking in deprived smokers are discussed. For reasons of space, only human studies are considered.
19.2 EFFECTS OF NICOTINE ON RESPONSE INHIBITION AND INTERFERENCE CONTROL 19.2.1 Antisaccade Tasks In the antisaccade task (Fig. 19.1), participants are instructed to make a rapid eye movement, a saccade, away from a sudden-onset peripheral target while avoiding a saccade toward it. The primary measure of inhibitory control on this task is the direction error rate, that is, percentage of trials on which the participant first looked toward the peripheral target. Additionally, latencies (RTs) of correct responses are often reported. Prosaccades are typically included as sensorimotor control condition. Numerous studies have provided evidence of beneficial effects of nicotine on antisaccade task performance.
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FIG. 19.1 Flowchart of an antisaccade task. In the antisaccade task, a rapid eye movement has to be made in the opposite direction of a peripheral stimulus (indicated here by a gray arrow). Antisaccade trials may be presented blocked, as in this example, or interleaved with prosaccade trials (saccades toward the target).
These effects have been reported with study designs differing considerably with regard to task characteristics (e.g., blocked or mixed antisaccade/prosaccade tasks), method of nicotine application (e.g., cigarette smoking after withdrawal, gum, nasal spray, injection, and patch), clinical characteristics (e.g., schizophrenia patients, schizotypal individuals, and controls), and smoking status (e.g., smoker and nonsmoker). Reductions in direction errors with nicotine have been observed in most (Dawkins, Powell, Pickering, Powell, & West, 2009; Dawkins, Powell, West, Powell, & Pickering, 2007; Depatie et al., 2002; Larrison, Briand, & Sereno, 2004; Larrison-Faucher, Matorin, & Sereno, 2004; Petrovsky et al., 2012, 2013; Pettiford et al., 2007; Powell, Dawkins, & Davis, 2002; Rycroft, Hutton, & Rusted, 2006; Schmechtig et al., 2013), but not all, studies (Ettinger et al., 2009, 2017; Rycroft et al., 2007; Thaker, Ellsberry, Moran, Lahti, & Tamminga, 1991; Wachter & Gilbert, 2013). Nicotine may also reduce antisaccade latencies (Bowling & Donnelly, 2010; Ettinger et al., 2009; Larrison et al., 2004; Larrison-Faucher et al., 2004; Petrovsky et al., 2013; Rycroft et al., 2006, 2007; Wachter & Gilbert, 2013), although not all studies have observed this effect (Depatie et al., 2002; Ettinger et al., 2017; Petrovsky et al., 2012; Schmechtig et al., 2013; Thaker et al., 1991). It should be noted that not all studies have reported latencies. While these effects are generally independent of clinical (schizophrenia, schizotypy, and control) and smoking (smoker and nonsmoker) status, there may be effects of baseline dependency with regard to antisaccade
performance (however, see Ettinger et al., 2017). For example, a study of schizophrenia patients showed greater improvement in low-performing patients (LarrisonFaucher et al., 2004). Additionally, Petrovsky et al. (2012) reported that nicotine reduced antisaccade errors in lowperforming but not in high-performing healthy participants, without affecting antisaccade latencies or prosaccade performance. Baseline dependency was also observed by Wachter and Gilbert (2013), who reported lower antisaccade but not prosaccade latency following a nicotine patch in poor and average (but not high) performing smokers, without any effects on error rates. To conclude, nicotine has beneficial effects on either direction errors or antisaccade latencies in the majority of studies. Given that most studies report no significant effects on performance on the prosaccade control task (Dawkins et al., 2007; Depatie et al., 2002; Ettinger et al., 2009; Larrison et al., 2004; Larrison-Faucher et al., 2004; Petrovsky et al., 2012; Pettiford et al., 2007; Schmechtig et al., 2013; Thaker et al., 1991; Wachter & Gilbert, 2013; however, see Ettinger et al., 2017; Petrovsky et al., 2013), these findings may reflect beneficial effects on the topdown control of saccadic eye movements.
19.2.2 Stop-Signal Tasks The stop-signal task (Fig. 19.2) is a measure of stopping or canceling a motor response. The task has been widely used to model the cognitive and neural mechanisms of
FIG. 19.2 Flowchart of a stop-signal task. In the stop-signal task, a response in a choice reaction task has to be stopped when a sudden-onset stop signal occurs. Here, the participant has to respond by indicating the direction of the target arrow (left or right) but has to stop this response when shortly after the target a stop signal (here, an arrow pointing up) is shown. The stop signal may also be an auditory stimulus.
19.2 EFFECTS OF NICOTINE ON RESPONSE INHIBITION AND INTERFERENCE CONTROL
response inhibition as well as deficits in inhibitory control in psychiatric and neurological patients. The key dependent variable is the SSRT, an indirect measure of the speed of the stopping process, but go RTs and percentages of correct responses are also reported in some studies. Beneficial effects of nicotine on SSRT have been observed in nonsmoking adolescents (Potter & Newhouse, 2004) and adults (Potter & Newhouse, 2008) with attention deficit hyperactivity disorder (ADHD); in nonsmoking young adults with high levels of impulsivity (Potter, Bucci, & Newhouse, 2012); and, weakly, in healthy nonsmokers (Logemann, B€ ocker, Deschamps, Kemner, & Kenemans, 2014b). Other studies, however, have failed to observe effects in healthy nonsmokers (Ettinger et al., 2017; Wignall & De Wit, 2011), smokers, (Bekker, B€ ocker, Van Hunsel, van den Berg, & Kenemans, 2005) or a combined sample of smokers and nonsmokers (Logemann, B€ ocker, Deschamps, Kemner, & Kenemans, 2014a). More consistent evidence of beneficial effects of nicotine on SSRT, however, comes from studies of smokers in a state of abstinence. Better performance following smoking as usual compared to abstinence was reported in most studies (Ashare & Hawk, 2012; Charles-Walsh, Furlong, Munro, & Hester, 2014; Tsaur, Strasser, Souprountchouk, Evans, & Ashare, 2015), although one study showed an increase in SSRT following smoking in smokers, suggesting disinhibition with nicotine (Austin, Duka, Rusted, & Jackson, 2014). Overall, it appears that nicotine improves stop-signal task performance in individuals with inhibitory impairments, that is, patients with ADHD and cigarettewithdrawn smokers. The experimentally controlled application of nicotine to healthy smokers and nonsmokers does not, however, appear to reliably enhance performance on this task.
19.2.3 Go/No-Go Tasks Go/no-go tasks (Fig. 19.3) are widely used to assess the ability to inhibit a dominant motor response. The most common measure of inhibitory control on the task is the (commission) error rate, that is, the percentage of responses on no-go trials, although studies have frequently also reported the RT of responses on go trials. While there is evidence of beneficial effects of cigarette smoking on no-go errors in smokers (Kozink, Kollins, & McClernon, 2010), most studies appear not to find significant effects of nicotine, including designs using cigarettedeprived smokers (Ettinger et al., 2017; Evans, Park, Maxfield, & Drobes, 2009; Giessing, Thiel, AlexanderBloch, Patel, & Bullmore, 2013; Harrison, Coppola, & McKee, 2009; Smucny, Olincy, Eichman, & Tregellas, 2015). One study of smokers with ADHD and smoking
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FIG. 19.3 Flowchart of a go/no-go task. In go/no-go tasks, the participant has to respond to a frequent go stimulus (here, a black circle) but withhold the response when a no-go stimulus is shown (here, a blue circle). In variants of the task, oddball stimuli are included. These also differ from the go stimulus in one stimulus dimension (e.g., color; an oddball stimulus in this example may thus be a green circle [not shown]) but have to be responded to like go stimuli.
controls observed that the patients made more commission errors when abstinent compared to a satiated state and more errors than the control group when abstinent (McClernon et al., 2008). There is also evidence of shorter (Giessing et al., 2013; Harrison et al., 2009; Houlihan, Pritchard, Krieble, Robinson, & Duke, 1996) and less variable (Houlihan et al., 1996) RTs on go trials with nicotine in nicotinedeprived smokers (however, see Ettinger et al., 2017; Kozink et al., 2010; Smucny et al., 2015). To conclude, the majority of studies have failed to provide evidence of beneficial nicotine effects on response inhibition in go/no-go tasks, and evidence is mixed with regard to effects on go RTs.
19.2.4 Stroop Tasks In the Stroop task (Fig. 19.4), the prepotent tendency to name a color word has to be inhibited; instead, the nondominant response of naming the print color of the word has to be performed. The Stroop task and its variants are widely applied in cognitive neuroscience, psychopharmacology, and psychopathology research. The key performance measure is the Stroop effect, that is, the difference in RTs or error rates between incongruent and congruent conditions.
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Woodward, 1991; Wesnes & Warburton, 1978; Wignall & De Wit, 2011) and patients with ADHD (Potter & Newhouse, 2004) and schizophrenia (Barr et al., 2008). There is also evidence that nicotine effects on Stroop performance may depend on CHRNA5 genotype ( Jensen et al., 2015) and smoker status, with beneficial effects observed in smokers but not in nonsmokers (Grundey et al., 2015). Overall, therefore, nicotine effects on inhibitory control in the Stroop task appear not to be reliable. The reasons for this are not clear, as both positive and negative effects have been obtained across smoker and nonsmoker samples as well as application methods (e.g., cigarettes in smokers vs controlled application of patches).
19.2.5 Flanker Tasks FIG. 19.4 Flowchart of a Stroop task. In the Stroop task, the participant is required to name the color that the word stimulus is printed in. The flowchart shows a randomized sequence of incongruent and congruent stimuli. Stimuli may also be presented blocked, that is, in separate lists of congruent and incongruent stimuli. Stroop tasks often also include a color bar condition to measure simple color naming time and frequently employ a central fixation cross before stimulus onset (not shown here).
A large number of studies have examined the influence of nicotine on the Stroop effect. Studies have employed both experimentally controlled applications and naturalistic methods involving cigarette smoking in smokers after variable durations of deprivation. Overall, the majority of studies have failed to observe beneficial influences of smoking or controlled applications of nicotine on the size of the Stroop effect (Cook, Gerkovich, Graham, Hoffman, & Peterson, 2003; Della Casa, H€ ofer, Weiner, & Feldon, 1999; Ettinger et al., 2017; Evins et al., 2005; Foulds et al., 1996; George et al., 2002; Ilan & Polich, 2001; Kos, Hasenfratz, & B€ attig, 1997; Levin et al., 1996; Mancuso, Warburton, Melen, Sherwood, & Tirelli, 1999; Parrott & Craig, 1992; Poltavski & Petros, 2006; Rusted, Caulfield, King, & Goode, 2000; Suter, Buzzi, Woodson, & B€ attig, 1983; Tsaur et al., 2015; Wesnes & Revell, 1984; Xu et al., 2007; Xu & Domino, 2000; Zack, Belsito, Scher, Eissenberg, & Corrigall, 2001). Other studies, however, have reported general enhancement of task performance (Atzori, Lemmonds, Kotler, Durcan, & Boyle, 2008; Azizian et al., 2010; Mancuso et al., 1999; Pomerleau, Teuscher, Goeters, & Pomerleau, 1994; Potter & Newhouse, 2008; Rusted et al., 2000; Zack et al., 2001). Yet, other studies have observed selective improvements in the Stroop effect in healthy individuals (Domier et al., 2007; Hasenfratz & B€ attig, 1992; Landers, Crews, Boutcher, Skinner, & Gustafsen, 1992; Provost &
Flanker tasks (Fig. 19.5) are popular measures of attentional interference. In flanker tasks, a response to a central stimulus is required, whereas peripheral flankers are to be ignored. The flanker effect describes the decrement in performance when peripheral flankers are incongruent with the central stimulus, compared to congruent or neutral conditions. A variant of the flanker task is the attention network test (ANT), which in addition to the conflict
FIG. 19.5 Flowchart of a flanker task. In this variant of the flanker task, the participant is required to indicate with a button press the direction of the central arrow (right or left) while ignoring the flanking distractors. This flowchart shows a randomized sequence of congruent and incongruent trials. Trials may also include neutral flankers and frequently employ a central fixation cross before stimulus onset (not shown here).
MINI-DICTIONARY OF TERMS
effect due to incongruent flankers taps alerting and orienting aspects of attention. While one study observed more efficient interference control on the ANT following a 21 mg nicotine patch in smokers with schizophrenia and smoking controls (AhnAllen, Nestor, Shenton, McCarley, & Niznikiewicz, 2008), other studies have failed to observe nicotine effects on flanker interference control in snuff users (Lindgren, Stenberg, & Rosen, 1996), nonsmokers (Ettinger et al., 2017; Kleykamp, Jennings, Blank, & Eissenberg, 2005; Wignall & De Wit, 2011), or samples of smokers and nonsmokers (Myers, Taylor, Salmeron, Waters, & Heishman, 2013). The study by Lindgren and colleagues, however, reported an overall reduction in RT and improvement in correct response rate following oral snuff, suggesting general performance-enhancing effects of nicotine (Lindgren et al., 1996). Flanker tasks have also been applied to investigate nicotine effects in smokers abstinent from smoking. One study observed that smokers had generally (irrespective of flanker congruency) higher RTs after overnight abstinence compared to ad lib smoking (Schlienz, Hawk, & Rosch, 2013). In another study, smokers showed reduced speeded accuracy during abstinence compared to smoking as usual (Schlienz & Hawk, 2017). Overall, therefore, effects of nicotine administration on interference control on flanker tasks are likely to be small, with most studies failing to report interference-specific effects or any effects at all.
19.3 CONCLUSIONS Overall, while there is evidence of beneficial effects of nicotine on inhibitory control, the literature is rather mixed. The most consistent effects are observed with the antisaccade task, where most studies report improvements in error rate and/or latency. The majority of studies also report beneficial effects on the SSRT, especially in impaired populations. The weight of evidence points against consistently positive effects on go/no-go, Stroop, and flanker tasks. These findings may be reconciled with earlier conclusions that nicotine improves more basic functions of attention, such as alertness and orienting, more strongly than the selectivity function of attention (Heishman, Kleykamp, & Singleton, 2010; Provost & Woodward, 1991). It should be noted, however, that improvements in basic, bottom-up attentional processing with nicotine may conceivably result in impaired top-down control (Ettinger et al., 2017; Rycroft et al., 2006), a pattern that is rarely observed. This suggests that nicotine may have positive effects on components of information processing that not only benefit basic attentional functions but also may be drawn upon in top-down control processes.
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The reasons for inconsistent effects on go/no-go, Stroop, and flanker tasks are unclear but may involve task factors, participant factors, and drug dose factors as well as their interactions. Task factors, such as inhibitory load, attentional load, or general task complexity, may contribute to variable nicotine effects across tasks. It is intriguing that effects appear to be more consistent on antisaccade and stopsignal tasks than on other tasks. This issue has not been systematically investigated. Designs that selectively vary relevant task features and inhibitory requirements are needed. Participant factors were found to play a role on antisaccade, stop-signal, and Stroop tasks in some studies. These factors include baseline performance (antisaccades), clinical conditions and/or level of impulsivity (stop-signal and go/no-go), genotype (Stroop), and smoking status (Stroop). These factors likely play an important role in explaining interindividual differences in nicotine response and interstudy differences in overall results (given differences in participant recruitment and selection between studies). Finally, dose dependency of nicotine effects on inhibition has been observed in some (Larrison-Faucher et al., 2004; Poltavski, Petros, & Holm, 2012) but not in other studies (Bekker et al., 2005; Foulds et al., 1996; Kleykamp et al., 2005; Meyers et al., 2015; Parrott & Craig, 1992). A related issue is that certain methods of nicotine administration allow a better titration than others (e.g., injection vs smoking) to achieve optimal dosages to meet individual participants’ needs. Generally, however, the issue of dose dependency merits further attention. Additionally, dose dependency may interact with participant and task factors.
MINI-DICTIONARY OF TERMS Antisaccade A saccade made in opposite direction to a sudden-onset, peripheral stimulus. Commission error A response to a stimulus that should not have been responded to. Flanker effect The difference in RT between incongruent and congruent conditions in flanker tasks. Reaction time (RT) The time, typically given in milliseconds, from stimulus appearance until the participant’s behavioral response. Saccade A rapid, conjugate movement of the eyes. Stop-signal reaction time (SSRT) The latency of the stopping process in the stop-signal task. The SSRT cannot be directly observed but is estimated. Stroop effect The interference of the meaning of a color word with the response to its print color. Naming the color in which a color word is printed is faster and less error-prone when the print color corresponds to the word (e.g., the word BLUE printed in blue) than when print color and word do not correspond (e.g., the word YELLOW printed in green).
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Key Facts of Inhibitory Control • The term inhibition denotes a heterogeneous construct that comprises a number of different phenomena in neuroscience and psychology. • In cognitive psychology, inhibitory control is a key executive function that refers to the ability to suppress actions, thoughts, and emotions. • Having to inhibit unwanted reactions, impulses, or emotions features prominently in everyday life. • Deficits in inhibitory control are observed in numerous neurological and psychiatric conditions. • Inhibitory control generally shows good temporal stability and significant heritability. • The neural networks underlying inhibitory control include the prefrontal cortex and its posterior cortical and subcortical projection targets. Summary Points • This chapter reviews the literature on nicotine effects on inhibitory control in humans. • The included inhibitory control paradigms are the antisaccade, stop-signal, go/no-go, Stroop, and flanker tasks. • Studies of both controlled applications (e.g., patch, tablet, injection, lozenge, spray, or gum) and cigarette smoking in deprived smokers are included. • The majority of studies of antisaccade tasks observed beneficial effects. • Beneficial effects on stop-signal tasks are observed in populations with inhibitory impairment. • Effects on go/no-go, Stroop, and flanker tasks are less consistent. • Overall, the literature suggests that nicotine effects on inhibitory control may be subtle, with task, participant, and dosage factors likely playing a role.
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