The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control: An EEG-Study

Transcription

1 Academiejaar Eerstesemesterexamenperiode The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control: An EEG-Study Masterproef II neergelegd tot het behalen van de graad van Master of Science in de Psychologie, afstudeerrichting Klinische Psychologie Promotor: Medepromotor: Prof. Dr. Gilles Pourtois Dr. Marie-Anne Vanderhasselt Svenja De Rore

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3 Preface The human brain together with cognitive and emotional processes have always intrigued me, which is also the reason why I wanted to do this particular EEG-study during my final master year. This preface provides me with the opportunity to thank all those who made this research possible for me. First of all, I would like to thank my co-promoter Dr. Marie-Anne Vanderhasselt for introducing me to this interesting project, for her education, guidance, valuable feedback and for her not to be underestimated moral support. I am also very grateful to my promoter Prof. Dr. Gilles Pourtois for his constructive comments and proposals regarding the placebo manipulation, his interpretations of my pilot study results, his EEGexpertise and his guidance and feedback during this whole project. Further, I would like to thank Jasmina Bakic for her guidance and help during the experiments, and for making my data-collection possible. Wim and Sammy, I would like to thank you for rereading and correcting my English and for your linguistic and grammatical advice. Svenja De Rore, Ghent University, 2014

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5 Abstract The Dual Mechanisms of Control framework postulates that cognitive control consists of two complementary components: proactive control, which reflects an anticipatory and top-down mode of cognitive control, and reactive control, which is a stimulus driven mode of cognitive control that is recruited as a reaction to interference or conflict detection. In our study we wanted to analyze the dynamics of cognitive control after a placebo manipulation, which consisted of a sham double-blind experimental design, a placebo cognitive enhancer and a manipulated numeral cognition task (NCT), by which we wanted to deceive participants performance perception. Cognitive control was tested by a Cued Emotional Conflict Task (CECT), during which we registered reaction times, accuracy scores and Event Related Potentials. Inter-individual variability in suggestibility or placebo manipulability was measured using two sources: a self report questionnaire and the performance measurements of the NCT. Results showed that participants who reported to experience more positive effects of the taken placebo, reacted significantly faster during the cued emotional conflict task. Moreover, these placebo related experiences mainly facilitated the reaction times during the cognitive control trials, that require more proactive control. Associated with proactive control, ERP-data of our control group also showed smaller CNV amplitudes during the cognitive control trials, which suggests increased working memory load or task related goal representation. Keywords: Placebo Proactive control Reactive control ERP topographic mapping analysis

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7 Contents Preface... 1 Abstract... 3 Introduction... 1 Cognitive Control and the Dual Mechanisms of Control... 2 Brain areas associated with cognitive control Variability in Cognitive Control Manipulating the Dual Mechanisms of Cognitive Control Summary Electro Encephalogram (EEG) and Event-Related Potentials (ERP s) Contingent negative variation (CNV) N N Summary and Research Questions Pilot Study Participants Procedure Results Discussion EEG-experiment Participants Procedure Material Cued emotional conflict task Numeral cognition task

8 Placebo cognitive stimulant Initial questionnaires Control questionnaire Apparatus Data reduction Statistics Results Design based groups: Placebo and Control Demographics and self-report data Behavioral data NCT-Based Groups ERP-Data Discussion References... 55

9 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 1 This current work is a study of cognitive control. These control processes are critical in working memory functioning and executive functioning (Braver et al. in Conway et al., 2007). Braver describes, cognitive control as so important, yet simultaneously so fragile and vulnerable to disruption (Braver, 2007, p.76). This may be one of the main reasons cognitive control has already been the subject of numerous works, studies and theories. A relatively recent and unifying theory which captures the dynamics of cognitive mechanisms of control, is the Dual Mechanisms of Control (DMC) model. The DMC theory postulates that there are two distinct mechanisms of control, proactive control and reactive control, which are both specialized and efficaciously activated and alternated. Proactive control is an anticipating or top-down mode of control, associated with online and sustained maintenance of goal representations in the working memory (WM). This control strategy minimizes interference and guides responses in a goal directed way, based on context information or cues. Reactive control, as the contrasting mode of control, is recruited as a reaction to interference or conflict detection, is stimulus driven, and is associated with transient brain activity. Within the present dissertation this theory will be used as the core model, serving as a frame of reference during research, and providing a coherent theory that takes into account the variability and complexity of cognitive functioning (Braver et al. in Conway et al., 2007; Braver, 2012). Former research concerning the dynamics of cognitive control focused on interindividual variability as well as intra-individual variability. To investigate intraindividual variability, researchers mainly manipulated task characteristics or conditions to analyze influences on the tradeoff of the control mechanisms. In case of interindividual variability, however, researches explored the influence of individual cognitive differences, like age or psychological state, on control strategy selection (Braver et al. in Conway et al., 2007; Braver, 2012). This current dissertation will address both sources of variability. First we will aim to modulate intra-individual conditions through expectation and cognitive state manipulation. Our goal is to create an expectation to influence the two components of cognitive control. Namely, we will ask the participants to take in a placebo pill and tell them that this pill will enhance their attention, concentration and response abilities profoundly. This way we want to achieve belief and confidence in the concentration and attention improving effects of the placebo pill and create an expectation

10 2 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control of enhanced cognitive abilities. We ll test the influence of this placebo manipulation on performances and brain activity, during a Cued Emotional Conflict Task (CECT) in which one needs to react as accurate and fast as possible according to a presented cue and the following presented face expression. More specifically, we are interested in the modulating effects of this placebo manipulation on proactive control and the tradeoff of proactive and reactive control, and its corresponding behavioral and neural changes. Event-Related Potentials (ERP s) will be registered during the CECT via an Electroencephalogram which measures changes or modulations in brain activity and control strategy. This EEG measurement is especially valuable because of its temporal capacities which enable us to discriminate sustained anticipating proactive processes and transient reactive mechanisms during cognitive control. Second, we re also interested in possible individual differences in cognitive control modulation after successful placebo manipulation. In other words, we want to investigate whether there is an inter-subject variability in the degree of control strategy modulation and explore individual factors that possibly influence the manner and the degree in which participants control pattern alters. This introductory section will be organized as follows. First I elaborate the Dual Mechanisms of Control framework. This is followed by a short outline of the brain areas associated with cognitive control. Afterwards I focus on fluctuations in cognitive control and expectation manipulation via placebo. In this section I shortly define placebo and placebo- effect and discuss two leading theories. Then I will review some relevant placebo studies in literature. After that, I briefly introduce the Electroencephalogram (EEG) measurement and its corresponding Event-Related potentials. I will conclude by summarizing and clarifying the research questions and hypothesis of this study. Cognitive Control and the Dual Mechanisms of Control Desired outcome of an action, as defined in cognitive tasks, as well as in everyday life, depends on control mechanisms, which are required for the selection of task relevant information and the suppression of task-irrelevant information (Marklund & Persson, 2012). Cognitive control is defined as: The processes behind the ability to configure itself for the performance of specific tasks through appropriate adjustments in perceptual selection, response biasing, and the on-line maintenance of contextual information

11 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 3 (Botvinick et al., 2001, p.424). It implies active, voluntary and controlled behavior; the opposite of passive, automatic, or stimulus-driven. Cognitive control facilitates the access to context-relevant stimuli while processing information. It is responsible for the maintenance of internal goal representations and coordinates perception and information processing in a goal directed manner (Wager et al. in Gazzaniga, 2004). Cognitive control can t be separated from the Working Memory (WM) which is generally defined as a system that comprises temporary storage and online manipulation and control of information (Smith et al., 1999; Miller & Cohen, 2001). In 1974, Baddeley and Hitch proposed to distinguish between short-term memory and working memory. They conceptualized an organization in a three-component system consisting of an attentional controller, the central executive and two subsidiary aiding systems, the sketchpad and the phonological loop (Baddely & Hitch in Osake et al., 2007). However, research on the organization of the working memory has progressively evolved into research on working memory functioning. Mainly recent studies aim to explore how WM works (Barrouillet & Camos in Osaka et al., 2007). In the context of the current dissertation, we are interested in working mechanisms of WM during cognitive control. The working memory s involvement in cognitive control includes maintaining, coordinating and updating the goals and rules of a task, needed for goal directed behavior. To achieve these goal directed operations of WM, attention on relevant information and processes increases, irrelevant information and processes are inhibited, subtasks and sequences are planned, attention is scheduled and managed to switch between tasks, contents of the WM are updated and representations are coded (Smith et al., 1999). A fundamental principle in cognitive processing is that it is competitive. As variety of possible neural pathways strife for execution in behavior, cognitive control is needed to guide cognitive processes towards goal directed behavior. Especially when stimuli are ambiguous and one must select the correct response while multiple responses are activated (Miller & Cohen, 2001). In this work we adduce a general theoretical framework, named the Dual Mechanisms of Control (DMC), to explain cognitive control. The model is applicable to understand variability in cognitive control. Its central hypothesis is that cognitive control operates through two separate yet complementary mechanisms: proactive control and reactive control. The DMC theory is a relatively recent, comprehensive and unifying framework which captures the variability and the

12 4 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control temporal dynamics of cognitive mechanisms of control. Its most prominent contribution as a theory of cognitive control and as a working memory theory in general, is that it is based on the intrinsic variability in cognitive control itself. In other words, it achieves to explain variability in cognitive processing in a comprehensive way by two independent and qualitative distinct modes of control that can be utilized in differing degrees, depending on internal states and external situation. Because it takes into account this variability and recognizes alternative mechanisms of control, the DMC serves as an appropriate framework to explore and research the complexity and dynamics of cognitive control. As previously mentioned, the DMC distinguishes two separate strategies or mechanisms of cognitive control, proactive control and reactive control. Proactive control is defined as: A form of early selection in which goal-relevant information or context is actively maintained in a sustained manner, before the occurrence of cognitively demanding events, to optimally bias attention, perception and action systems in a goaldriven manner (Braver, 2012, p.106). In the DMC-theory the term context is used to refer to internally represented task-relevant information that can influence, prime or bias action systems, information processing, perception, attention, memory and emotion. (Braver et al. in Conway et al., 2007; Braver, 2012). Proactive control implies anticipation, active goal retaining and it prevents interference before it occurs, which results in a top-down regulation of attention and processing. Its counterpart, reactive control, is defined as the attention which is recruited as a late correction mechanism that is mobilized only as needed, in a just-in-time manner, such as after a high interference event is detected. It relies upon the detection and resolution of interference after its onset (Braver, 2012, p.106). Precedent to an interference event, the reactive control system is relatively uncontrolled thus making bottom-up inputs more influential. Concerning behavioral consequences or the influence of control mode selection on performances, the DMC postulates that proactive control increases performance optimization and accuracy, and reduces response interference or conflicts. Additionally, it is assumed that the reactive control strategy is more susceptible for response interference and would result in slowed reaction times because goal representations have to be reactivated post probe presentation (Braver, 2007; Braver, 2012; Speer et al., 2003).

13 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 5 We conclude this section with a short comparison of proactive and reactive control in terms of computational and processing properties, temporal dynamics and finally neural activity (Braver, 2007). Considering computational properties, proactive control is future-oriented, it addresses early selection and implies preparatory attention. Reactive control on the other hand is past-oriented, it implies interference resolution and is responsible for late corrections. Therefore, reactive control depends more on the triggering events for mobilization and reactivation of the goal representations. Concerning the information processing, proactive control has a strong goalrelevant focus and involves global control effects while in reactive control there is increased goal-irrelevant processing and more item-specific control. Consequently, proactive control is less sensitive for other potentially relevant bottom-up information. On the temporal dimension, proactive control is sustained and is activated prior to the imperative stimulus. Adversely reactive control is rather transient, so it is activated after the imperative stimulus and it decays away quickly post to that stimulus. Finally, the two mechanisms have a different neural topography, with proactive control correlating with activation in the lateral prefrontal cortex and the midbrain dopamine system, while reactive control with the anterior cingulated cortex, the LPF, the medial temporal lobe and other brain areas that are activated by association or memory retrieval (Braver et al. in Conway et al., 2007; Braver, 2012). These different brain regions, and their relation to proactive and reactive control, will be discussed in the next paragraph. Brain areas associated with cognitive control. The involved brain areas within cognitive control are the Prefrontal Cortex (PFC), the Anterior Cingulate Cortex (ACC), the Medial Temporal Lobe (MTL) and the midbrain Dopamine system (DA). Even though the brain areas involved in proactive and reactive control overlap, their activation and implementation patterns are temporally distinguishable, which corroborates the DMC model and its early and late mode of cognitive control (Braver et al. in Conway et al., 2007, Braver, 2012). Next, we make an overview of brain areas most prominent in the functioning of DMC.

14 6 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control The prefrontal cortex (PFC). The frontal cortex is engaged during top-down processing and when cause of action is internal, goal related, rather than externally driven. The PFC actively maintains goal representations, finds the means to accomplish them, and guides neural activity towards goal achieving performances. Other properties of the PFC involved in DMC are the ability to sustain activity and avoid interference, the ability to integrate and converge sensory and behaviorally relevant information, the flexibility to adapt to new tasks or demands, and the connectivity or capacity to interact with other brain areas and to receive and send feedback signals (Miller & Cohen, 2001). More concrete, the lateral prefrontal cortex area is involved in executive functions and cognitive control and is recruited in both reactive and proactive control (Botvinick et al., 2001; Duncan & Owen, 2000; Braver et al. in Conway et al., 2007, Osaka & Osaka in Osaka et al., 2007). Switching between proactive and reactive is highly flexible, depending on individual factors and task conditions (Braver et al., 2009). When someone controls in a proactive manner, the current theory implies a sustained activation in the lateral PFC during the whole retention interval, from goal formation or context presentation until goal realization. This sustained lateral PFC activity would be accompanied by sustained activation in the posterior cortex. The interaction between the frontal and posterior cortex is assumed to support top-down or proactive cognitive control and the update and maintenance of goal representations (Braver et al. in Conway et al., 2007; Braver, 2012; West et al., 2012). It is presumed to be the dorsolateral prefrontal cortex area (DLPFC) which is involved in the anticipatory maintenance, representation and manipulation of context information or task related demands (D Esposito et al., 1999a; D Esposito et al., 1999b; Barber & Carter, 2005; Braver et al. 2007; Savine & Braver, 2010). In essence, it is assumed that the DLPFC maintains and up-dates comprehensive representations of the task context by encoding task relevant rules and associated responses, stimulus features and conflict (Mansouri et al., 2009). More activity in this region implies more top-down control and leads to less conflict and smaller interference effects (MacDonald et al., 2000; Braver et al. in Conway et al., 2007)

15 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 7 Reactive control implies recurrent transient activation of the lateral prefrontal area, in other words a repeated reactivation of goal representations instead of continuous maintenance. Specifically, the reactive mode of the DMC would be associated with ventro-lateral prefrontal cortex (VLPFC) activity, which is typically associated with detection and resolution of interference or conflict (Braver et al. 2007; Braver, 2012). It is assumed that this VLPFC supports response inhibition processes and updating of prepared action plans in order to engage in an alternative and correct response (Levy & Wagner, 2011; Braver, 2007). On the other hand, reactive control is associated with transient VLPFC activity, including activity in other additional brain regions. This activation pattern is considered to reflect a bottom-up manner of cognitive control, initiated by interference or conflict detection or by strong associative paths and episodic associations (Braver et al. in Conway et al., 2007; Braver, 2012). Essentially, it is assumed that the anterior VLPFC is activated during controlled retrieval of contextual relevant information that is needed to guide behavior in a goal-directed manner (Souza et al., 2009). Other prefrontal regions involved in cognitive control are the mid-lateral PFC, the mid-frontal gyrus and the inferior frontal gyrus (IFG). The mid-frontal gyrus (MFG) and the mid-lateral PFC are associated with memory suppression as they become more active when individuals get better trained in inhibiting items where they are forbidden to think about. Along with this increased activation, the activity in the hippocampal area decreases (De Pisapia & Braver, 2006). Also the right inferior frontal gyrus (rifg) is involved in reactive and proactive operations. The rifg is recruited when valuable, relevant and important cues or stimuli are detected and task representations have to be activated (Brass et al., 2005; Hampshire at al., 2010; Levy & Wagner, 2011). Temporal dynamics in the rifg suggest that proactive and reactive control efficiently alternate depending on the availability of context. Therefore, the role of the rifg can flexibly shift from a reactive role, when its activity is mostly stimulus-driven and episodic retrieval of context information is needed for response selection, to a preparatory role, when cues enable anticipation and a top-down, tonic maintenance of context information is required (Marklund & Persson, 2012; Levy & Wagner, 2011, Derrfuss et al., 2004).

16 8 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control Medial temporal lobe. The hippocampus/medial temporal lobe complex (PTL) supports the PFC functioning via raid, associative connections. When the reactive mode of control is recruited, the hippocampal or medial temporal lobe is involved. Transient hippocampal activation is observed when interference or conflict needs to be resolved and context information is not presented in the WM. In this case reactive control is obtained by activation of long-term representations, episodic memories or associations and hippocampus or MTL recruitment (Marklund & Persson, 2012; Braver et al. in Conway et al., 2007). The midbrain. Cognitive control needs a dynamic balance between cognitive stability and cognitive flexibility. Failure to accurately update context or goal representations will result in perseverative behavior, whereas failure to appropriately maintain them will lead to distractibility. In the accomplishment of this balance, the dopaminergic midbrain is fundamentally involved. The dopamine (DA) neurotransmitter modifies cognitive performances and working memory by prefrontal cortex regulation where it influences dopamine receptors. More specifically it is assumed that DA supports the online stabilization of task relevant representations and the update of this context representations when new information is presented. (Cools & D Esposito, 2011). In the review of Cools and D Esposito s (2011) it is suggested that high levels of dopamine receptor stimulation in the PFC, benefits cognitive stability but is disadvantageous for cognitive flexibility, while high DA levels in the striatum is beneficial for cognitive flexibility. According to DMC-theory, phasic outburst of dopamine in the PFC modulates the neurons in the PFC which makes it possible to actively retain the task relevant context information and to facilitate its update. When context information occurs, a strong burst of DA activity would enable the PFC to engage, while relatively low but tonic DA activity during the delay is needed to maintain the information and prevent interference or decay. This results in stable information processing without interference by task-irrelevant stimuli. So when proactive control is engaged, DA activity changes as context

17 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 9 information or cues are presented, whereas in reactive conditions DA does not intervene in the PFC (Braver et al. in Conway et al., 2007; Braver, 2012). Secondly, the DA system has an important function in learning by reinforcement or rewards. In reinforcement learning, the assumed goal is to associate a stimulus of an action with a reward and learn to act in function of the greatest reward. According to the gating hypothesis, a phasic dopamine release is needed to allow relevant signals to establish new context representation and to update the represented goals, because without this phasic release of dopamine the PFC will stay unaffected by new valuable stimuli. Under the reinforcement learning theory of dopamine function, a positive rewardprediction error, or a state of which the current value is better than expected, is associated with a phasic burst in dopamine activity (Montague et al., 2004). In other words, when motivational incentives are presented and during periods of reward feedback, the activation in the DLPFC is enhanced by midbrain dopaminergic engagement (Savine & Braver 2010). This enables DA to regulate the entrance of the WM and to coordinate when goal maintenance or updating is appropriate. Summarized, the PFC supports the representation and maintenance of the information provided by the context, while the DA system regulates the access and sustained maintenance of this information (Braver et al. in Conway et al., 2007; Braver 2012). The anterior cingulate cortex (ACC). In several studies anterior cingulate cortex (ACC) activity is observed when conflict occurred. More specifically, engagement of the ACC is associated with tasks that require the overriding of dominant responses, tasks that require selection out of a set of equally possible responses, and tasks that involve the commission of errors. (Botvinick et al., 2001; West et al., 2012, Van Veen & Carter, 2002). Furthermore, the ACC-activity is also associated with negative feedback and reward learning (West et al., 2012). In a review of Botvinick and colleagues (2004), it is suggested that the ACC fulfills an evaluative and monitoring function regarding the response outcomes. Herewith, the ACC is sensitive to conflict and reacts to situations that indicate a reward reduction. Additionally the ACC infers information about effort and demands, and monitors the need for mental control, concentration and commitment.

18 10 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control According to the DMC, the anterior cingulate cortex is centrally engaged in reactive control because of its conflict detecting properties (Carter et al., 1998). In other words, the ACC detects conflicts over a short-time scale and immediately engages reactive control strategies to resolve the detected conflict or interference. Secondly, its activity also serves as a signal for increased need of proactive control. In fact, it integrates repeated interference over a long time to interact with the dorsolateral prefrontal cortex and increase conflict anticipation and proactive control (Carter et al., 1998; Carter & Van Veen, 2007; Burgess & Braver, 2010). De Pisipia s and Bravers research (2006) showed how high interference or conflict occurrence is associated with increased sustained activity in the lateral PFC, while activity in different PFC areas and the ACC is associated with conditions where interference and conflict occurs less frequent. The first condition mobilizes proactive control and an increased active maintenance of context representations, which leads to a decreased engagement of reactive control and less ACC activity. In the second condition where conflicts or incongruent trials are less likely to occur, reactive control and ACC-activity is involved at the time of conflict presentation (De Pisipia & Braver, 2006; Braver et al, 2007). Variability in Cognitive Control As previously mentioned, there would be intra-individual and inter-individual variability in cognitive functioning of the dual mechanisms of control. According to Braver and colleagues, varying application of proactive and reactive control strategies depends on several factors, for instance task related factors, the state of the individual, the cognitive capacities and the personality (Braver et al., 2007; Braver, 2012). A first possible source of inter-personal variability in cognitive control is personality. As suggested by Braver et al. (2007, 2012), stable personality features would affect the chosen way of cognitive control. There is assumed to be a link between a BASpersonality, reward sensitivity, activity of the dopamine system and proactive control on the one hand, and a BIS-personality, conflict and punishment sensitivity, and activity in the ACC on the other hand. Individuals who scored high on BIS-personality used more reactive control and were very vigilant for conflicts. This was associated with an high ACC-activity. Individuals with an high BAS-score were more likely to anticipate and to prepare their reactions. They used more proactive control. Here there was less ACC

19 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 11 activity to be observed (Braver et al., 2007, Braver, 2012). Likewise, based on other studies of anxiety and cognitive efficiency of Fales and colleagues (2008), Braver infers an association between anxiety and a decreased capability to control proactively. Cognitive skills would be a second influential factors of inter-individual variability in the Dual Mechanisms of Control. Compared to persons with a low degree of fluent intelligence, people who score high on fluent intelligence tests perform more accurate and show less interference effects on cognitive control tasks. Additionally there was increased delay-related activity in the PFC observed in people with high fluent intelligence while in people with low fluent intelligence increased activity after probe onset was observed when this went along with conflict or interference. Consequently it is assumed that high fluent intelligence can be associated with more proactive control and less reactive control, contrary to low fluent intelligence (Gray et al., 2003; Burgess & Braver, 2010). Other psychological factors that influence the variability in control strategy usage are strength of habits or response biases, arousal level and available WM capacity (Braver et al., 2007; Braver, 2012). Finally there are the group factors that can be considered as source of interindividual variability in cognitive control. In this regard Braver and colleagues (2009) report that elderly people and people who suffer from schizophrenia show less anticipating goal related activation and more reactive correcting activation. On a neurological level this pattern of activity can be observed in the PFC. Differences in patterns of control would be observable in children, adolescents, individuals who suffer from ADHD, individuals with schizophrenia, and individuals who are depressed. The Dual Mechanisms of Control is therefore very useful to explain changes in cognitive control. (Braver et al., 2007; Braver, 2012) Regarding intra-individual variation, small manipulations of cognitive tasks and their consequences on performance and brain activity could be explained by the theory of Dual Mechanisms of Control (DMC). Overall reactive control is sub-optimal in conditions with weak perceptual information and the reaction selection parameters are indistinctly or vaguely defined. Proactive control strategies are less ideal when the retention intervals are long and there are no reliable predictive contextual cues. Other factors are length of preparation time, expectation of proactive interference, expectations of memory load, and demands on speed or/and accuracy (Braver et al., 2007). Because of

20 12 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control the sustained and consistent engagement of proactive control over several trials, this control mechanism requires a lot of our metabolic resources. Given this relatively big metabolic consumption and the metabolic limitations, proactive control will be more involved when the expected benefits are greater and when interference expectancy is high (Burgess & Braver, 2010). Besides this influence of task consequence expectancies, interference expectancy also has an important influence in a way that when interference expectancy is high, proactive control is more engaged then reactive control. On the other hand, reactive control operates well when interference is unexpected, infrequent or inconsistent. Furthermore, when memory load expectancy is high, reactive control is more recruited instead of proactive control. (Braver et al., 2007; Braver, 2012) In the current study we aim to manipulate intra-individual conditions and analyze subsequent variations in the application of proactive and reactive control. We ll change task conditions by introducing the participants to a psychopharmacological experiment along with placebo cognitive stimulants. We expect this task manipulation to alter interference expectancies and task consequence expectancies. Therefore we assume changes in cognitive control will occur and participants will apply modified strategies of cognitive control. In addition we can assume participants will respond differently on the placebo manipulations. Therefore we expect inter-individual variation between participants, depending on their state, mood and suggestibility. Manipulating the Dual Mechanisms of Cognitive Control As described previously, we aim to manipulate intra-individual conditions via a placebo procedure. By subjecting participants to a sham psychopharmacological experiment with placebo cognitive stimulants, we want to change the expectancies about cognitive abilities and modulate the relationship and interaction between the two mechanisms of control. We are particularly interested in the intra-individual change in proactive/reactive control tradeoff, and investigate how changes in proactive control application influences reactive control during these manipulated task conditions and altered performance expectancies. In concrete, we aim to manipulate individual mindset and task conditions via placebo manipulation. Doing this, we want to analyze the effect of a placebo cognitive enhancing drug on proactive control and the resulting interaction between proactive and

21 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 13 reactive control. By telling participants that they are taking an active drug that will on the one hand enhance attention, concentration, and ability to react, and will also decrease impulsive reactions on the other hand, we aim to manipulate cognitive performance expectancies and interference expectancies, hence causing modulation of cognitive control strategies and brain activity. Placebo in Latin literally means to please or I shall please, (Moerman, 2002; Price et al., 2008; Shapiro & Shapiro, 1997). In 1964 Arthur K. Shapiro, a placebo specialist, proposed the following definition of placebo and the placebo effect: A Placebo is defined as any therapeutic procedure (or a component of any therapeutic procedure) which is given (1) deliberately to have an effect, or (2) unknowingly and has an effect on a symptom, syndrome, disease, or patient but which is objectively without specific activity for the condition being treated. The placebo effect is defined as the changes produced by placebos (Shapiro, 1964, p. 712). In sum the placebo-effect potentially occurs as a changed response or a sense of benefit felt by a patient, after nonactive or inert treatment is given while the patients believe to have received an effective and active treatment. It is related to the perception of therapy administration and is a psychobiological phenomenon that is generally attributed to a range of mechanisms, including expectation and conditioning (Beneditti et al., 2005; Beneditti et al., 2012; Price et al, 2005). Nocebo is known as the counterpart of placebo and refers to adverse or negative effects, caused by an inert treatment because the person believes it to have a negative or harmful outcome (Price et al., 2005). Taken together, placebo and nocebo can both be conceptualized as meaningful responses, associated with individual experiences, expectancies, beliefs, learning history and relations (Beneditti 2013; Jakovljevic, 2013). Concerning the beliefs, it is argued that the patients belief that medical treatment is taking place and that the procedure or drug works adequately, is crucial to trigger placebo response. Other important features that influence treatment effects and side-effects are the clinical setting, believable and ensuring communication between doctor and patient about the drug, medical features and its effects and the doctor-patient relationship (Evans, 2003; Moerman, 2002). Additionally it also seems that color, number and administration route of the drug has an influence on the placebo response. Concretely, two placebo pills seem to work better than

22 14 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control one, placebo shots seem to have more effect than the oral placebo, and red placebo pills seem to work better as a stimulant than bleu ones (Moerman, 2002). The influence of context: Conditioning effects and expectancy manipulation. Many theories try to explain the effect and its mechanisms. Generally, the main theoretical conceptualizations of the placebo-effects are the classical conditioning perspective and the expectancy perspective (Geers et al., 2005b; Beneditti, 2008). In the conditioning perspective the own experience of taking the medication can influence the placebo response, which is interpreted as a result of associative learning (Colloca et al., 2010). The drugs, active ingredients or treatments that work, even if you have never experienced it before, are seen as unconditioned stimuli. The unconditioned response is the effect or the improvement after treatment administration. The methods, medical regimen or techniques that are frequently paired with this drug or treatment, are the conditioned stimuli. Conditioning occurs when the conditioned stimuli coincides with an effect of the unconditioned stimuli. In this approach, previous experience with the unconditioned stimuli or similar stimuli is important and a learning process is assumed to be involved (Geers et al., 2005b; Price et al., 2008; Evans, 2003). The unconditioned reaction to drugs or treatments, for example relieve of pain, is assumed to be evocable by the conditioned stimuli after repeated classical conditioning. This way, the clinical context (color or shape of a pill, white coats or medical precautions) can also elicit the therapeutic response. This conditioned response is what would be called the placeboresponse (Steward-Williams & Podd, 2004; Price et al.,2008; Geers et al., 2005b; Colloca et al., 2010; Beneditti, 2012). The associative learning process causing placebo-response, is assumed to imply two phases: (1) learning or derive the association between the contextual elements or conditioned stimuli and the effects of the treatment or unconditioned stimuli, (2) the ability to remember or recall the outcomes for a certain time span. The latter is shown to be influenced by the amount of conditioning trials or parings between the conditioned stimulus and the unconditioned stimulus (Colloca et al., 2010). The expectancy perspective postulates that the anticipation of the predicted or suggested outcome leads to the production of that particular outcome or reaction. In other

23 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 15 words, the placebo generates an effect because one expects it to. These expectations can be generated by verbal instructions, emotional arousal, the interaction with the careproviders, previous experiences or environmental clues (Steward- Williams & Podd, 2004; Price et al., 2008; Geers et al., 2005; Beneditti, 2012). The goal of this study is to bias participants expectancies via a placebo pill, in such a way that the placebo group will believe the cognitive enhancing effects of the pill and expect improved attention, concentration and cognitive capacities, along with decreased task interference. In other words, we expect a shift in control mode due to these placebo mediated bias of participants interference and cognitive capacity expectancies. In the light of these interference expectations, Burgess and Braver (2010) performed an interesting study in which they manipulated interference expectancy via small modifications in a recent negatives paradigm (RNP). Results showed that when interference expectancy was high, participants controlled in a more proactive way, while in the low expectancy conditions reactive control was recruited instead of proactive control (Burgess & Braver, 2010). In this current dissertation we also aim to manipulate interference expectancy and aim to create low interference expectancies within the participants who get a placebo cognitive enhancing pill. Considering the results of Burgess and Bravers experiment, we may infer the hypothesis that participants who take in a placebo pill, of which it is predicted to enhance attention and concentration and decrease impulsive reactions, consequently will expect less task interference and will recruit less proactive control which makes them control more in a reactive way. This increased reactive or stimulus driven mode of control will consequently proceed in less interference or conflict anticipation and preparation, which will eventually result in decreased efficiency and performance optimization. In the end we would expect this to cause decreased accuracy and increased reaction time during cognitive tasks (Burgess & Braver, 2010). Additionally, another study, relevant to the current dissertation, manipulated expected WM load across conditions. Speer and colleagues (2003) recruited 65 participants to perform a memory task in which they manipulated memory load expectancy. When low WM load was expected, participants controlled more in an anticipatory or proactive manner, while when high WM load was expected, the pattern of control was more reactive. As we consider these interesting results, we may infer a second either contrasting hypothesis that in our current dissertation placebo manipulation of

24 16 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control expected attention and concentration will create the expectancy of improved WM capacity, leading to increased application of proactive control strategies and improved performances (Speer et al., 2003). In sum, both hypotheses contribute equally to this dissertation, keeping in mind that the goal of this study is to bias participants expectancies via a placebo pill, in such a way that the placebo group will believe the cognitive enhancing effects of the pill and expect improved attention, concentration and cognitive capacities, along with decreased task interference. In other words, we expect a shift in control mode due to these placebo mediated bias of participants interference and cognitive capacity expectancies. Our current conclusion postulates that contextual factors, previous experiences and expectancies can have an influence on proactive control usage and the resulting tradeoff between proactive and reactive control. As for now, shifts in cognitive mode of control can go both ways, whereas increased proactive control concurs with decreased reactive control and increased reactive control concurs with decreased proactive control. Regarding this dissertation, we can assume that the expectancies will be more important than conditioning in placebo-effect generation. Since we instruct the participants that they will take a cognitive enhancing pill, similar to Ritalin, chances are little they will have already experienced effects of this kinds of pills in the past. To compensate this in a way, we will describe the effects they are supposed to experience by comparing it with the effects of caffeine and nicotine. In the following sections we will outline additional relevant studies to complement current hypothesis. Psychoactive placebo manipulation. Regarding stimulatory agents like caffeine and nicotine there are a few placebo studies examining the effects of expectancies on cognitive performance. The placebo manipulation in those studies usually affects subjective measurements in a significant manner but in respect to the objective measurements of performance the results are inconsistent. A modest study by Anderson and Horne (2008) examined the placebo effect of caffeine on sleepy people. In the experiment a small group of participants, consisting of 16 young healthy adults, were asked to limit their night s sleep to 5 hours and had to perform on a psychomotor vigilance test. In the placebo-group the participants were told that they were about to consume a super type of coffee that would keep them alert for 90

25 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 17 minutes, while they actually consumed one cup of decaffeinated coffee. They were also explicitly told about the potential effects of the coffee, as in that a better performance was expected. This placebo manipulation resulted in an improved performance on the psychomotor vigilance task, despite the non-significant subjective ratings for a decrease in sleepiness. Specifically, the number of errors and the mean reaction time was reduced significantly (Anderson & Horne, 2008). Second, Juliano and colleagues (2011) found similar results using nicotine as placebo agent. Their study used a balanced placebo design to investigate the influence of dose expectancy manipulation on reaction time and accuracy during a Rapid Visual Information Processing (RVIP) task after smoking a placebo or nicotine cigarette. During the RVIP task participants have to react as quickly as possible whenever they detect three consecutive odd or three consecutive even numbers on the screen. Overall, the results show that dose expectancy influences subjective rewarding effects and the experienced cognitive enhancement. Regarding the objective measurements they found a small but significant effect of dose expectancy on accuracy or number of false alarms during the RVIP task. The participants who were told that they were smoking a nicotine cigarette produced fewer errors of commission or false alarms compared to the participants who were told that they were smoking a placebo cigarette, regardless of the actual dose. A study by Harrell and Juliano (2012) found contradictory results during a similar 2x2 factorial experiment in which they manipulated smokers expectancies in order to investigate the influence of modulated expectancies RVIP task performances. In contrast to the study of Juliano and his colleagues this study found no effects of expectancy manipulation on sustained attention during the RVIP, potentially due to performance-based payment. Another relevant study was performed in 2009 by Harrell and Juliano, in which participants consumed either a coffee that contained 280 mg caffeine or a placebo decaffeinated coffee. Half of the participants was instructed that the coffee would enhance their performance while the other half was instructed that the coffee would impair their performance on a RVIP task. Paradoxical with the outcome expectations of the study they found a performance improvement in those participants who consumed a placebo but were instructed that the coffee would impair them compared to participants who consumed a placebo but were instructed to be cognitive enhanced by the coffee. The authors of the study postulate that this may reflect attempts to compensate

26 18 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control for the expected impairment, by putting more effort in the task. It gets even more complicated when we take into account the self-report data. These data reveal that participants of the enhance group reported more motivation while the participants of the impair group reported more effort to resist the instructed drug effects. Finally, a more recent study by Parker and colleagues (2011) researched the effects of a placebo cognitive enhancing drug on prospective memory. The placebo manipulation in this study resulted in a significantly higher report of cognitive effects in subjects who were told they got an active cognitive enhancing drug. Those subjects who received a placebo cognitive enhancing drug reported more enhancements of their senses, quicker responses and better concentration than subjects who were told they got an inactive drug. Moreover the participants who received the placebo and active drug instructions were significantly more accurate on a prospective memory task, compared to the control group which was told that the participants were receiving an inactive drug. The placebo group also showed higher reaction times during an ongoing word categorization task, which they had to perform during the proactive memory task, compared to the control group. These results were interpreted as indicative for greater monitoring for prospective memory cues in subjects from the placebo condition (Parker et al., 2011). Finally a study by Parker and colleagues (2008) showed in a similar way that psychotropic placebos are able to reduce the misinformation effect during a test. In this study 96 participants were told about a fictitious drug R273 that would be safe and effective in increasing mental alertness, cognitive functioning and the ability to detect and distinguish changes in the visual field. They were told about the mechanisms of action by a scientist who in his explanation also mentioned the word memory. Additionally the participants were also warned about some physiological side effects. Afterwards the participants were weighted and those weight records were fictitiously used to divide the group participants into a placebo group and a control group. Both groups received a placebo drug but in the placebo group the participants were told they were getting an active drug and in the control group the participants were told they received an inactive drug. After the expectancy manipulation and drug administration all the participants had to watch a series of 62 slides picturing a shoplifter stealing some items from a bookstore. After this series of slides the participants were asked to read a

27 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 19 summary that contained misleading information about the previously seen slides. Finally the participants had to perform a memory task in which their memory of the actual slides was tested, and in which was measured how much they were misled by the post-event summary. The results of the study show that the participants from the placebo group, who were told to receive the active drug, were more resistant to misleading suggestions during the memory test, compared to the participants of the control group. However, both groups were equally accurate on the control items, those items that were described accurately in the summary. Additionally, resistance to the misinformation effect in the placebo group was interpreted as a result of a more stringent monitoring during the memory test as the participants took longer to respond on misleading test items compared to the control group. In sum, most studies using psychoactive placebos show clear subjective improvement and most of them also show placebo mediated increases in accuracy and monitoring. Otherwise, the study of Harrel and Juliano (2009) showed how instructions of expected impairment after placebo coffee or caffeine administration, resulted in improved performances, compared to the condition in which they were instructed that caffeine will enhance their performances. Consequently it is interpreted that participants from the impair condition tried to compensate the expected impairment and put more effort during the task. Inversely we can infer the possible hypothesis that an instruction of expected cognitive enhancement during placebo administration could result in less effort and impaired performances because of participants expectations of drug compensation. Summary. The Dual Mechanisms of Control framework, first described in 2007 by Braver (Braver, 2007), emphasizes the intrinsic variability of cognitive control in terms of two qualitative and temporal distinct modes of control; proactive control mechanisms and reactive control mechanisms. Proactive control reflects top down and anticipatory active maintenance of task goals, and it is also associated with sustained activation in the lateral PFC, while reactive control reflects bottom-up or stimulus driven control mechanisms and is associated with ACC mediated transient lateral PFC activity.

28 20 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control As outlined in section , varying application of proactive and reactive control strategies depends on several factors. Regarding the current study, it is aimed to create modified expectancies and task conditions. It is assumed that these manipulated conditions will guide attention and influence the application of proactive and reactive control. Subsequently we will investigate how changes in proactive control application influences reactive control and how inter-individual differences in degree of proactive control are modulated after successful expectancy manipulation. First, research on the influence of expectation manipulation on pattern of cognitive control clearly showed how manipulation of interference expectancy or WM load expectancy can result in a shift of mode of cognitive control. Specifically, high interference expectancy and the expectancy of low WM load led to increased proactive control and consequently less reactive control usage. Regarding this dissertation we assume that placebo cognitive enhancing pill administration can result in altered interference expectancies as well as in altered WM load expectancy. Consequently we assume that proactive control will either increase or decrease and that this changes in proactive control usage will eventually result in a contrasting shift in reactive control. Taken together the outlined results, which are rather insufficient and undetermined, we withhold two contrasting hypotheses for this dissertation and its placebo experiment. First, placebo cognitive enhancing pill administration may result in increased proactive control, and by interaction in decreased reactive control usage. Specifically we can infer in case of increased proactive control, there will be less interference and consequently reactive control will decrease. As for their performances, we will expect performances to be optimized and be more accurately compared to a situation of decreased proactive control and increased reactive control usage. Secondly, we can hypothesize that used placebo manipulation may result in decreased proactive control and subsequently in an increase of reactive control. In case of this placebo mediated shift to increased reactive and decreased proactive control, we expect participants to be more impaired by interference or conflict and perform slower compared to the increased proactive control situation.

29 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 21 Electro Encephalogram (EEG) and Event-Related Potentials (ERP s) The present dissertation will use electroencephalograms (EEG) and event-related potentials (ERP s) to analyze brain activity after the placebo manipulation and during the cued emotional conflict task. Electroencephalography is a set of method of measurement and analyses of encephalogram (EEG) or brain-related electrical potentials recorded from the scalp (Kropotov, 2009, p. 6). An action potential is a temporary change in the neuron membrane potential and it occurs when information is transmitted by a nerve and ions are exchanged across the neuron (Sanei & Chambers, 2007). These recorded signals are then filtered and balanced to extract the ERP s from the continuous EEG (Picton et al, 2000). Event related potentials are local field potentials or EEG recorded during a psychological task and averaged over trials of the same category. In the course of averaging, spontaneous positive and negative fluctuations cancel each other, leaving averaged potentials associated with stages of information processing in the brain (Kropotov, 2009, p. 6). The millisecond temporal resolution of scalp EEG is very adequate for precise and accurate temporal measurements of brain activity occurrence. This high temporal resolution of the EEG-technique is especially important to detect and discriminate processes of proactive control on the one hand, and to analyze proactive and reactive control mechanisms and its related brain activity on the other hand. Because the ERP s are measured at scalp level, using electrodes or sensors which are applied on the scalp, the spatial resolution of the ERP measurement is rather limited (Picton et al., 2000). This is partly compensable by using a larger cluster of electrodes. In this study, a 128- channel EEG is used. This multi-channel recording uses an array of 128 electrodes, densely covering the scalp, to estimate the inter-cerebral locations of the brain activity and processes (Picton et al., 2000). The set of data trials will be averaged time-locked to the cue event and time-locked to the target event. In sum, we will record and take into account the neural activity during the CECT task. The components of neural activity or ERP s that are relevant for this dissertation will be outlined in the following section. These ERP s can be named on the basis of their direction of their deflection (positive or negative) and peak latency, such as the N450 and the N2, or named after their functional meaning such as the Contingent Negative Variation (CNV), the Error Related Negativity (ERN) and the Error Positivity

30 22 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control (Pe). These ERP s will be recorded, analyzed and considered in our study of placebo influence on the dual mechanisms of cognitive control. Contingent negative variation (CNV). Contingent negative variation (CNV) is a slow ERP that has increased brain negativity during response preparation or during the interstimulus interval (Nagai et al., 2004; Weerts & Lang, 1973; Kropotov, 2009). These preparatory operations associated with the CNV, can endure for several seconds or more and occur in absence of observable behavioral changes when a subject is preparing for a stimulus or a response (Kropotov, 2009). It is generally elicited by a cueing stimulus (S1) and is associated with response anticipation and preparatory processing (Nagai et al., 2004), and working memory processes (Kropotov, 2009). The CNV is assumed to consist of an O wave and an E wave. The O wave peaks shortly after the cue or the warning signal (S1) and reflects an orienting response, while the E wave peaks later and is related to the anticipation of the imperative signal (S2) on which one needs to react or respond (Loveless & Sanford, 1975). Taking into account the anticipatory characteristics of the CNV it is presumed that all brain structures that are involved in the upcoming task will be activated during CNV, which is why topographical distribution of CNV is rather complex (Brunia et al., 2011). CNV generation has been associated with activity in the thalamus, cingulate cortex, bilateral insula and fronto-pariëtal areas including the superior and medial frontal area, the fronto-parietal lateral brain areas, the extrastriate visual cortex, the DLPFC, the premotor, motor and sensory cortex, and the supplementary motor area (Nagai et al., 2003; Gomez et al., 2007). Overall it is presumed that, given its spatio-temporal organization, CNV indicates endogenous attention recruitment. Additionally the temporal dynamics of the DLPFC involvement during CNV suggests an important role of WM and goal maintenance (Onoda, 2004). Studies show how CNV amplitudes decrease with increasing memory load or increasing response interference (Gevins et al., 1996; McEvoy et al., 1998; Tecce, 1972). In accordance decreased CNV components are also associated with increased reaction times (Mc. Evoy et al., 1998). In connection to the dual mechanisms of control, we can presume that CNV is related to proactive control and top down processes of response anticipation.

31 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 23 N450. The N450 has a later onset and peak than the N2 and is also assumed to be generated by the ACC. It can be defined as a negativity over the fronto-central region that peaks at approximately 450 msec, that is also sensitive to manipulations of cognitive control. (Folstein & Van Petten, 2008, West & Alain, 2000). The amplitude of the N450 is suggested to covary with the contextual demands of tasks and more specifically with the magnitude of interference. The N450 amplitude seems to be modulated by proportion of interference or conflict in such a way that, in situations with a low proportion of conflict, the amplitude of the N450 will increase when conflicting information is presented (West & Alain, 2000). Additionally, the study of Larson and colleagues (2009) showed sensitivity of the N450 component for conflict in the current trial but no significant conflict adaptation effect of the N450 since there were no differences in N450 amplitude as a function of previous-trial context (Larson et al., 2009). However this finding is rather contradictory considering the conflict-context adaptability of ACC activity and the recent findings of West and Bailey (2012) that show an interaction effect between the current and previous trial for the N450. So regarding the conflict adaptation effect of N450 there are still some clarification to be made. Regarding the temporal dynamics it is indicated that conflict information or interference elicit fronto-central peaks around 400 msec, which is relatively close to the timing of the response. Around 200 msec later, an increased theta power and sustained phase coupling with the LPFC can be observed, which is assumed to reflect the recruitment of the prefrontal areas and more cognitive control in order to resolve the response conflict (Hanslemayr et al., 2008). In sum, it can be concluded that N450 is accompanied by goal interference, ACC activity and modifications in cognitive control. Given temporal proximity to response timing, its relatedness to interference and conflict, and its generation source, N450 recordings can serve as an indicator of reactive control, when temporally determined around target onset. N2. The N2 component is a negative wave peaking between 200 and 350 ms post stimulus onset and is sensitive to cognitive control (Folstein & Van Petten, 2008). Monitoring of ongoing processing is critical in cognitive control and the ERP component

32 24 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control N2 is presumed to exhibit this monitoring function. As mentioned above, it is suggested that ACC is engaged in conflict monitoring and this area is presumed to generate frontocentral N2 component during correct conflict trials when interference or distracting information activate conflict representations prior to the response (Yeung et al., 2004; Carter & Van Veen 2007). The anterior N2 is evoked by several tasks that are related to response and strategic monitoring, like the go-no-go task, the stroop task, flanker task and stop signal paradigm (Folstein & Van petten, 2008). In general it is hypnotized to be associated with response inhibition and response-conflict detection (Nieuwenhuis et al., 2004). Additionally, reliable conflict adaptations effects were observed for the N2 amplitude and those larger N2 conflict adaptations effects seemed to be related to higher degrees of executive functioning and attention. More specifically, when incongruent trials or conflicts occur frequently, more cognitive control will be engaged, which will minimize later conflicts and result in a decrease of the N2 amplitude. Therefore larger adaptation to incongruent trials, as indexed by N2, is related to adjustment of cognitive control strategy (Clayson & Larson, 2012). In the study of Zhang and Luo (2009) they examined the effect of placebo analgesia, established from pain alleviation, on emotion perception during a task where pictures had to be watched and rated on unpleasantness. The experiment showed that when placebo analgesia effect was reinforced during one condition, this went along with expectations that altered the level of negative emotion during a subsequent emotional rating task. During the experiment ERP's were recorded and the results of these recordings showed an increased N2 amplitude when transferred placebo effect was established. Analyses suggested that this amplified N2 component might reflect increased top-down control or suppression of negative emotions, induced by positive expectations (Zhang & Luo, 2009). Considering the temporal dynamics of the DMC framework and the relatively broad activation pattern associated with N2, we infer that N2 recordings can serve as an indicator of both proactive control and reactive control. As mentioned above, N2 ERP s are associated with response conflict detection and is assumed to be generated by the conflict monitoring ACC. Consequently N2 recordings, temporally determined around target onset, can serve as indicator of reactive control usage. On the other hand, N2 ERP s

33 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 25 are also associated with conflict monitoring, top-down control and the activation of conflict representations prior to response. N2 recordings temporally locked to cue onset, can thereby serve as indicator of proactive control. Summary and Research Questions The goal of this study is to influence the dual mechanisms of cognitive control via altered task conditions and modified interference expectancies. Proactive an reactive control will be investigated after placebo cognitive enhancing pill administration. The placebo manipulation in this experiment includes a false medical admission phase, a sham cognitive enhancing pill and a false medical procedure prior to drug administration in which a sham PhD Doctor of Medicine performs some physical measurements. Cognitive control will be measured during a Cued Emotional Conflict Task (CECT) throughout which ERP s are registered via EEG- measurement. The CECT provides participants a cue, by which they can prepare themselves to respond in a certain way to a target photo of a happy or a sad face. In particular the cues ask the participants to react with the opposite emotion of the target, the actual emotion of the target or it can just ask the participants to press the according press button. Concerning participants behavior, reaction time and accuracy are registered. Using these particular task conditions, we want to investigate if a sham psychopharmacological experiment and placebo stimulants can influence cognitive control and cause intra-personal adaptations with regard to proactive and reactive control usage. Given the undetermined and ambiguous results of current research, we withhold two hypotheses in which we both expect a placebo mediated shift in cognitive strategy of control, leaving the direction of the modification in mechanisms of control undecided. First it can be hypothesized that the participants in the placebo group perform, according to their placebo manipulated expectations and control, more proactively in comparison to the control group. Essentially, we can expect that the participants of the placebo condition control more proactively, relative to the control group, and that this subsequently would result in optimized preparation and continuously adjusted goal directed behavior to facilitate successful completion if the CECT cued goal. Because of this increased usage of the proactive mode of control we expect less interference and conflict. Regarding behavioral data we expect less errors of commission and smaller RT. Concerning neural

34 26 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control data we expect decreased amplitudes within the cue-locked CNV and N2 components on opposite trials versus actual trials in the placebo group, relative to the control group. For the ERP s time locked to targets we would expect decreased N2 and N450 amplitudes. These results would support the hypothesis of increased proactive control and decreased reactive control in response to placebo manipulation of cognitive performance expectancies. Second, we can hypothesize that placebo manipulation of cognitive performance expectancies in the placebo cognitive enhancing condition would result in more reactive control, more interference or response conflict, and consequently in weaker performances because of assumed placebo pill compensation. For the ERP s time locked to cues we would expect a decreased N2 on opposite trials versus actual trials, relative to the control group. For the ERP s time locked to targets we would expect a compensatory increased N2 and N450. Correspondingly, behavioral measures would show more errors and longer reaction times during these opposite trials. These results would support the hypothesis of diminished proactive control and increased reactive control in response to placebo manipulation of cognitive performance expectancies. Additionally we want to examine inter-personal variability and investigate if this manipulation has equal effects among participants. Meaning we are interested in how personal differences influence the degree in which one adapts its cognitive control strategy and degree of proactive control usage during placebo manipulated conditions.

35 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 27 Participants Pilot Study A group of eight healthy psychology students were recruited online to participate in the study via the online system of Experimetrix. They were informed that they would participate in a pharmacological study. All were asked to give their written informed consent and were paid 30 euro for their participation. The study was approved by the university s ethical committee. Procedure The participants were randomly assigned to the control condition or the placebo condition. In the placebo condition the participants were asked to perform the CECT after administration of a placebo cognitive enhancer, while in the control condition they had to perform CECT-task after administration of a control capsule. In both conditions the participants were told about a new drug Equasim. They were informed about the working mechanisms of the drug and its effects on concentration, attention and response control. It was explicitly told that more accurate and faster responses during the CECT-task were expected after drug administration. Then they were introduced to a sham Doctor of Medicine who asked the participants to read a drug information form and to complete an admission form with medical relevant questions. Afterwards an invalid medical check-up was performed, which included the measurement of the participants heart rate, blood pressure and temperature. At the end they were asked to sign for cognizance and they had to pick a card to determine their condition. This grouping procedure was manipulated as they were already randomly assigned to a certain group in advance. In the placebo condition the participants were asked to administrate the drug Equasim and they were told it would take 15 minutes for the drug to be effective. The participants of the control condition were asked to take a control pill without active ingredients. Next, all participants had to fill out psychological questionnaires to register their anxiousness, positive and negative affect, mood, and attention. At the end all participants performed the CECT-task and filled in a final questionnaire with VAS-scales to indicate their expectancies and beliefs about the drug and medical procedures. Later, all participants

36 28 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control were debriefed about the real experiment premeditation by . They were also asked to mail their reflections about the experiment and the placebo manipulation procedure. Results Qualitative analyses of the feedback and post-test questionnaires revealed some deficiencies in the pilot procedure. All post-test reports of the participants in the placebo condition reflected a dysfunctional placebo manipulation. General comments were (1) absence of clinical setting, (2) absence of experienced effects and (3) implausible experimental design. Regarding the experimental design, most participating students questioned the overt grouping procedure. Discussion Post-pilot reports showed a dysfunctional placebo manipulation, caused by multiple factors. First, feedback reflected influence of the setting as the experiment took place at a psychology faculty and not in a medical setting. Placebo effect and the administration of psychotropic medicines is proven to be very complex and dependent of multiple factors, including clinical setting and trust in the physician and psychiatric medicine (Benediti, 2013). Despite of this deficit in our procedure, we were not able to change the treatment setting. Compensating this shortcoming, we decided to eliminate medical students and psychology students from the study, to minimize the risk that participants look through the real goal of the experiment. Second, absence of experienced effects was reported as an important factor contributing to the failure of the placebo manipulation. The placebo procedure used in our pilot study depended solely on verbally induced expectations, as previous conditioning with cognitive stimulants is unlikely. These verbal suggestions clearly were insufficient to elicit placebo related expectancies in participants. However, placebogenerating expectancies are also believed to be acquired by associative learning or implicit learning procedures (Voudouris et al., 1990; Martin-Pichora; 2011). Furthermore it has been repeatedly discussed that placebo effect can be interpreted as a learning phenomenon based on prior experiences (Voudouris et al., 1990; Amanzio & Benedetti,1999; Colloca et al., 2010). Given this information, we decided to simulate the

37 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 29 expected effects in order to shape the experience of cognitive enhancement. To realize this, we used a manipulated numeral comparison task by which we aim to create the illusion of enhanced cognitive abilities. Third, the post-pilot feedback showed that the placebo procedure of our study was rather transparent. Participants explained they thought it was rather unusual for a so-called clinical trial, to give explicit information about grouping and the nature of the administered pill. Considering this, we could conclude no manipulation of performance expectancies or interference expectancies took place. The overt grouping procedure as well as the explicit suggestions, were not efficacious as placebo manipulation and thereby not able to manipulate the participants mindset and expectancies. Therefore we decided to describe the experiment as double-blind, suggesting that neither the participant nor the researchers knew which pill was administered. On the one hand, this double blind information would imply complete elimination of explicit expectancies, meaning performance related expectancies have to be shaped implicitly. As described earlier, we would try to evoke this by using a manipulation task which simulates enhanced cognitive capacities. On the other hand, double-blind administration procedures and associated informed consents are assumed to be particular preconditions. Previous studies were able to demonstrate complex psychological effects of double-blind administration, associated to the Hawthorne effect (Kirsch & Weixel, 1988; Kaptchuc, 2008; Jakovljevic, 2014). Concealment and knowledge of double blind administration can produce opposite reactions, compared to the expected drug responses (Kirsch & Weixel, 1988; Bergmann et al., 1994; Kaptchuck, 2008). Either way, we assume that double blind drug administration will influence the participants mindset or expectancies, causing alterations in cognitive control strategies and application. These improvements were tested and approved during the second pilot study, in which five people participated. Participants EEG-experiment A group of 24 healthy individuals aged were recruited online to participate in the study via the online system of Experimetrix. All were asked to give their written informed consent and were paid 30 euro for their participation. The university s ethical

38 30 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control committee approved the study. The selection criteria restricted the participants to right handed people, without a current or past diagnose of ADHD or depression. Psychology students or medical students were excluded from the experiment, given the difficulties during the pilot. The demographic data of all participants can be seen in the Result section, table 1. Procedure Each participant was scheduled for a test moment via the online system Experimetrix. The experiment was described as a pharmaceutical-psychological study in which a new cognitive enhancing drug was tested. Participants were told that a medical check-up would precede and that drug administration was save and risk free. During the test moment all participants had to perform the same task, the cued emotional conflict task (CECT). A double blind experimental design was made up and the participants were told that neither they, nor the experiment leaders knew which pill they would take. They were promised to receive a debriefing mail in which it would be revealed if they took the real drug or a control pill. In reality, all participants got placebo pills. The participants were told about the fake new drug Equasim. They were informed about the working mechanisms of the drug and its effects on concentration, attention and response control. It was explicitly told that more accurate and faster responses during the CECT-task were expected after drug administration. Then they were introduced to a sham Doctor of Medicine who asked the participants to read a drug information form and to complete an admission form with medical relevant questions. Afterwards an invalid medical check-up was performed, which included the measurement of the participants heart rate, blood pressure and temperature. Afterwards the participants had to perform the pre-placebo, difficult version of the numerical cognition task. When finished the doctor told them they were medically approved to participate. Then the participants were asked to sign for cognizance and had to take a pill. They were informed that the active drug would take 15 minutes to be effective. Next, they had to fill out psychological questionnaires to register their anxiousness, positive and negative affect, mood, and attention. When finished, they had to perform the post-pill administration and easy version of the numeral cognition task. This way we aimed to deceive participants performance perception so that they experience performance facilitation and expect to have taken the active drug. Finally all

39 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 31 participants performed the CECT-task and a final easy version of the numeral cognition task. They also filled in a final questionnaire with VAS-scales to indicate their expectancies and believes about the drug and medical procedures. Later, all participants were debriefed about the real experiment premeditation by mail. Material Cued emotional conflict task. We used the cued emotional conflict task, programmed by E-prime and previously validated in a study of Vanderhasselt and colleagues (2012). This task allows us to differentiate between the cue-induced anticipating processes and the processes of cognitive control. Each trial of the cues emotional conflict task embodies three phases. See Figure 1 for a schematic overview. First a cue word is shown during 500 msec, followed by a fixed inter-stimuli interval of 2500 msec in which a black screen is presented, and finally the target stimulus is presented for another 500 msec. There are three possible cues to be distinguished. If the presented cue reads actual, the participants have to press the button that corresponds with the presented emotion during the target phase. If opposite is presented, the participants are asked to press the button that corresponds with the opponent emotion of the presented one. Finally, the participants have to press a third button, the one with the word press on, as soon as the target is presented on the screen. These trials operate as control condition to analyze the differences between groups in global reaction time. The allocation of the labels; positive, negative, and press, are balanced along the three buttons across participants. The cue is followed by a fixed interval that varies between 2000 msec and 3000 msec, paced by 250 msec, during which a black empty screen is displayed. Afterwards a picture of a face is presented. The pictures that are used are the 14 faces of Karolinska Directed Emotional Faces data set. The collection of used faces exists of seven men and seven women, each expressing a happy or sad face. These faces were selected by normative ratings if the expression was correctly categorized by 75 percent of the group of raters and was scored higher than six on scale of nine (Goeleven, De Raedt, Leyman, &Verschuere, 2008).

40 32 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control Figure 1 Schematic overview of the Cued Emotional Conflict Task (CECT). The experiment consisted of 30 practice trials, in which five faces were used that didn t belong to the experimental collection of pictures, followed by 288 test trials. The test trials were divided into eight blocks of 36 trials. Every cue was combined with every facial expression (3 cues x 2 faces), and each combination occurred in six trials of every block. The reaction time of the practice trials was used to calculate the threshold of late responses in the experimental blocks. In case the reaction time (RT) exceeded this threshold, too slow appeared on the screen for 250 msec as feedback. This threshold for reaction time was recalculated after each block to take possible evolutions of performance into account, and was scored higher than six on a scale of nine (Goeleven et al., 2008). Numeral cognition task. A numeral comparison task (NCT) was used to manipulate the subject s performance experience and to induce placebo expectations. During the task participants have to evaluate if the number on the screen is larger or smaller than fifty and have to press the associated key. Based on the numeral distance effect, two versions of a numeral comparison task were created with E-prime: an easy and a difficult NCT. De distance effect implies it is easier to compare numbers, which are numerically far apart, compared to numbers which are numerically close to each other. This effect would be caused by

41 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 33 human number representation (Moyer & Bayer, 1976). It is theorized that the representation of certain number activates neighboring number representations in the brain, making it difficult to discriminate between simultaneously activated numbers (Moyer & Bayer, 1976). Applied to the NCT, items were divided in difficult and easy items, according to numerical distance. The easy items had a distance of more than 16 numerical units away from fifty (1-32 or ), and the difficult items had a distance smaller than 16 units (33-49 or 51-66). The difficult version of the NCT was composed of 42 difficult items and 8 easy items. The easy version entailed 42 easy items and 8 difficult items. If the presented number is bigger than 50, participants have to press 1, if the number is smaller than 50, they have to press 2. The answer-interval lasts 1000 msec. First the number is shown 500 msec, followed by an inter-stimuli interval of 500 msec in which a black screen is presented. If the participant gives a wrong answer, a feedback screen which reads Wrong is presented. There s no feedback for reaction time. Placebo cognitive stimulant. As placebo cognitive stimulant pill, containing 160 mg of Mannitol, is used. The participants are given this capsule and a glass of water prior to the EEG-measurement. They are instructed that this medication is a cognitive enhancer and that it will be fully effective approximately 15 minutes after oral administration. Initial questionnaires. Prior to the CECT, the 30 participants will have to fill out the Dutch version of the Spielberger Trait-state Anxiety Inventory (STAI, Spielberger, 1983), the Positive and Negative Affect Schedule (PANAS, Watson, Clark & Tellegen, 1988), the Beck Depression Inventory (BDI, Beck, Steer & Brown, 1996), and the Attention Control Scale (ACS, Derryberry & Reed, 2002). These measurements were used as an index for anxiousness, positive and negative affect, mood, and attention. All used questionnaires have good psychometric properties.

42 34 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control Control questionnaire. After finishing the CECT, all participants will have to perform a final easy version of the NCT and fill out a control questionnaire. These latter questionnaire serves as a manipulation check, queries possible experienced symptoms and contains six Visual Analogue Scales (VAS). Question 1 to 4 are partly based on the Credibility/Expectancy Questionnaire (CEQ, Devilly & Borkovec, 2000). An important difference with the CEQ is that its questions are future oriented, measuring placebo expectancies and believes, while we changed the formulations in way that the questions queries post-hoc experiences and believes of the taken pill. The first question asks participants to evaluate the pharmacological and medical procedure for accuracy, responsibility and reliability. For the second VAS participants have to rate how much confidence they have in the effects of the given pill. For question 3 they have to indicate the extent to which they experienced positive effects on attention, concentration and responsiveness. Question 4 probes if it was more or less difficult to perform the CECT, additionally question 5 asks if more or less effort was required to perform the CECT. Finally, for the last VAS they have to rate if they would buy the taken drug to do exams. Last two questions were included after post-pilot reviews and reports. Apparatus During the computerized cognitive task, continuous EEG will be acquired using a 64-channel Biosemi Active Two system ( From these concurrently recorded EEG-signals, the average reactions to the stimuli is determined, which serve as Event Related Potentials. The cue-locked ERP s, measured after cue presentation, will be analyzed as a measure of proactive cognitive control. The targetlocked ERP s, measured at the moment of target presentation, will be analyzed as a measure of reactive cognitive control. A Geodesic Sensor Net System (Electrical Geodesic, Inc. [EGI[)will be used to record this 64-channel electroencephalography (EEG) within an electrically and acoustically shielded room (sampling rate 250 Hz; analog filter 0, Hz; recording reference vertex; impedance < 45 kω).

43 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 35 Data reduction The cued emotional conflict task includes 288 trials. Each cue is presented 96 times, each target is presented 48 times. We withheld only those target trials in which participants responded correctly and within the specified time range. Electroencephalography recordings were analyzed using Brain Vision software (Brain Products, Gmbh) and filtered offline with a 30-Hz low-pass filter (12dB/Octave). Large artifacts were removed and an independent component analysis was used to correct for eye blinks, horizontal eye movements, electrocardiogram and 60-Hz noise. Next, corrupted channels were replaced by spatially weighted linear interpoletions (Hjorth nearest-neighbors algorithm) and cue-locked (-500 msec to 3000 msec), target-locked (- 250 msec to 1500 msec) and response-locked segments were extracted. Finally a semiautomatic artifact rejection procedure was ran (maximal amplitude: ± 100 μv; within-segment absolute amplitude difference: 150 μv; gradients: 50 μv ) and further preprocessing was performed, consistent with prior ERP studies from the laboratory. We defined groups in two different ways. First we used external data from a previous CECT-experiment, performed in 2012 by Vanderhasselt and colleagues (2013). Within this experiment a group of 20 healthy adults performed the CECT-task, while 128- channel ERP s were recorded. No manipulations were conducted. We used both behavioral and ERP-data from this study, as control measurements to compare with our current data. Data from our current study will be referred to as placebo, data from the previous study will be referred to as control. Next we used the data from our numeral cognition task to define groups within the placebo dataset. The difference score was calculated between the first difficult version of the NCT and the subsequent easy version of the NCT, both for accuracy and response time. Between those two versions a pill was administered. Doing this we could discriminate a group participants who became less accurate and a group of participants who became slower during the second NCT, which is supposed to be the easier version. To analyze differences in suggestibility and manipulation related changes in mind set or behavior, we used two sources. First we used the speed and accuracy measurements from the manipulation task or numeral cognition task as an objective measurement of suggestibility. Besides we gave participants a control questionnaire at the end of the

44 36 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control experiment. This questionnaire checked confidence and expectancies of participants with respect to the medical procedure and placebo pill. These ratings on visual analogue scales will be used as an subjective measurement of suggestibility. Statistics Separate cue (actual, opposite) x emotion (happy, sad) x Group (control, placebo) Repeated Measures analyses of variance (ANOVAs) were performed for accuracy scores and response times. To compare means and explore possible group differences we performed Independent-Sample T-tests for all cues and emotions. In order to distinguish the individual trials or cue/valence combinations and to calculate their difference scores we performed Paired-Sample T-tests. Results Design based groups: Placebo and Control Demographics and self-report data. Within the placebo group 24 participants were recruited, within the control group 20 participants were recruited. From the placebo group one participant was excluded after outlier analyses and one was excluded because of insufficient ERP-data. From the control group one participant was excluded because of missing values and one was excluded because of an extremely high BDI-score. This leaves us 22 participants in the placebo group and 18 controls. The groups differed significantly on age (F(1, 38) = , p < 0.001), total STAI-score (F(1, 38) = 9.265, p < 0.01) and total BDI-score (F(1, 38) = , p < 0.01). Groups didn t differ on gender (χ 2 = 0,077, p=0,529) or education level (χ 2 = 1.828, p = 0.401). Table 1 summarizes the means and standard deviations for the demographical and questionnaire data. Notwithstanding the significant difference between both groups for total BDI and STAI-score, we won t use these data as covariates because the difference isn t relevant from a qualitative point of view.

45 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 37 Table 1 Demographics, BDI and STAI: Means and Standard Deviations Group; Mean (SD) Characteristics Placebo group, n = 22 Control group, n = 18 Age (6.807) (14.309) Gender, female no. (%) 15 (68.18%) 13 (72.22%) Total STAI (3.217) ( 5.801) BDI (3.595) (2.358) Behavioral data. First we performed a Repeated Measures Analysis of covariance (rancova) for the reaction time measurements (Cue (actual, opposite, press) x Emotion (happy, sad, press) by Group (placebo, control) with Age as covariate). The results show a significant main effect of Age (F(1, 37) = 8.774, p < 0.01). In particular we observe larger response times when age increased. No significant between subject effects were found for Group (F(1, 37)= 0.262, p = 0.612), neither we found significant interactions with the factor Group (Fs < 2.5, ps > 0.12). Mean reaction times by Group are presented in table 2. To specify the effects of age we wanted to further analyze the individual effects on cognitive control by excluding the press condition from our rancova. Doing this we found that reaction times of the cognitive control measurements ( opposite and actual trials) still varied significantly with Age (F(1, 38) = , p < 0.01). Table 2 Reaction times by group: Means & Standard Deviations Group; Mean (SD) Placebo group, n = 22 Control group, n = 18 RT Actual Happy ( ) ( ) RT Actual Sad ( ) ( ) RT Opposite Happy ( ) ( ) RT Opposite Sad ( ) ( ) RT Press Happy (72.340) ( ) RT Press Sad (53.428) ( )

46 38 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control For further analyses we use the epsilon corrected within subject effects, given the violated assumption of sphericity. Considering these corrected effects we find a significant linear main effect of Cue (lower bound F(1, 37) = , p < 0.01) on reaction time. Subsequent Paired Samples T- test shows significantly different mean reaction times between all three cues. Looking at the direction of this effect, as displayed in table 3 and figure 2, we can infer participants react slowest at the opposite trials and fastest at the press trials. Table 3 Reaction times by Cue: Estimated Marginal Means and Standard Error Reaction time: Estimated marginal means (St. Error) Opposite (34.696) Actual (29.727) Press (12.856) Figure 2 Reaction times by Cue: Estimated Marginal Means and Standard Error Estimated marginal mean Reaction Time 200 Opposite Actual Press Estimated marginal mean

47 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 39 Secondly we performed a rancova for accuracy levels (Cue (actual, opposite, press) x Emotion (happy, sad) by Group (placebo, control) with Age). Tests of betweensubject effects showed no effects of the independent condition Group (F(1, 37) = 1.700, p = 0.200), neither were there significant interactions with this factor (Fs < 2.5, ps > 0.12). We can infer that accuracy did not vary with Group assignment 1. Again accuracy scores did vary significantly with Age (F(1, 37) = 0.025, p = 0,867). Epsilon corrected within subject effects show a significant within-subject effect of Cue (lower bound F(1, 37) = 8.374, p < 0.01). Participants generate most errors during the opposite trials and least during the press trials. The estimated marginal means for accuracy scores are presented in table 4 and figure 3. Paired sample T-tests further clarify that most conditions differ in a significant way, except for the actual/sad and opposite/sad trials (t(39) = , p = 0.823) together with the actual/happy and press/happy trials (t(39) = 1.586, p = 0.121). Table 4 Accuracy scores by Cue: Estimated Marginal Means and Standard Error Accuracy: Estimated marginal mean (St.Error) Opposite (0.329) Actual 1.7 (0.291) Press (0.205) 1 Purely exploratory we performed Repeated Measures Analysis of Variance (ranova) for Cue (Actual/Opposite/Press) and Emotion (Happy/Sad), by Group and without Age as a covariate. These exploratory analysis showed a significant between subject effect of the factor Group on reaction time measurements (F(1, 38) = 7.567, p<0.01). Regarding the descriptive statistics, we can infer that the Placebo group responded faster compared to the control group. As for accuracy, the exploratory analysis revealed no significant between subject effects of the factor Group (F(1, 38) = 2.408, p=0.129).

48 40 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control Figure 3 Accuracy scores by Cue: Estimated Marginal Means and Standard Error 3,5 3 2,5 2 1,5 1 0,5 0 Estimated marginal means Accuracy Opposite Actual Press Estimated marginal mean NCT-Based Groups As described previously, we used two sources to investigate suggestibility within the placebo group; ratings on a subjective control questionnaire and performance measurements during NCT, also referred to as the manipulation task. During the latter task our aim was to deceive participants into the experience of enhanced performances, by giving them a difficult version pre-drug administration and two easy versions postdrug administration. Analyzing the relation between the objective NCT-measurements and subjective ratings on the control questionnaire. We analyzed the relation between the performances on the NCT and the ratings on the control questionnaire via a Pearson correlation analysis. Results showed significant correlations between ratings on the third control question (CQ3) and reaction times during the first easy version (ρ = , p < 0.05) and the second easy version of the NCT (ρ = , p < 0.05). No significant correlation was found with reaction times for the preplacebo difficult version of the NCT (ρ = , p = 0.293). This latter control question 3 probes the experienced effects of the taken pill on attention, concentration and responsiveness. Concerning the direction of the correlation, faster reaction times on the

49 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 41 easy versions of the NCT, performed post-pill administration, are associated with higher ratings for the experienced effects. Subsequently we can interpret that participants who react faster on the first and second easy version of the NCT reported to experience more positive effects of the administered pill on attention, concentration and responsiveness. Analyzing the effects of experienced benefits, probed by question 3, on CECT performances. We performed different repeated GLM analyses for the reaction times and the accuracy scores on the CECT (Cue (actual, opposite, press) x Emotion (happy, sad). We used ratings on CQ3 as the a covariate because earlier analyses show that ratings on this particular question represent individuals performance manipulability and placebo experiences in a reliable way. Results revealed no significant between subject effect of these CQ3 ratings on reaction times during the CECT (F(20, 1) = 2.387, p = 0.138). Multivariate tests did reveal a significant three-way interaction between the factors Cue and Emotion, and the ratings on CQ3 as covariate (F(2, 19) = 4.536, p < 0.05). For the interaction interpretation we performed a contrast analyses to compare the effects the individual levels of the factor Cue combined with the levels of the factor Emotion. Results demonstrate that reaction times differ significantly according to the combined levels of the factors Cue and Emotion (F(1, 20) > 6.5, p < 0.02). To interpret these condition differences, we generated reaction time means for each condition and adjusted them for the effect of the covariate or ratings on CQ3. Table 5 summarizes these adjusted means.

50 42 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control Table 5 Adjusted Means Reaction times CECT Cue Emotion Mean Std. Error Opposite Sad 823,591 51,434 Happy 819,023 61,124 Actual Sad 670,841 51,634 Happy 586,909 35,448 Press Sad 252,341 11,145 Happy 259,205 15,635 We can infer that participants react slowest during the opposite trials and fastest during the press trials. Considering the factor Emotion, it takes participants longer to react within the Sad -trials, compared to the Happy-trials. Although we notice opposite effect within the press conditions, were participant react slower for Happy -trials. Taken in account the three-way interaction of the factors Cue and Emotion with the covariate CQ3, we notice that higher ratings, indicating the experience of more positive effects of the pill, generates smaller reaction times during the CECT. In interaction with the factors Cue and Emotion we notice that a relatively larger effect of CQ3-ratings on the opposite/happy (B = ) and actual/sad trials (B = ). It seems that with increasing experience of positive effects, participants respond faster on trials that require a Sad response ( actual/sad and opposite/happy ). Figures 4 show the scatter plots that represent the effect of the covariate CQ3 within each condition. As for accuracy, ratings on CQ3 had no significant effect on the CECT accuracy scores (F(1, 20) = 1.169, p = 0,292), neither was the covariate CQ3 involved in a significant interaction.

51 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 43 A B C D E F Figure 4 Scatter plots Reaction times CECT by CQ3 positive experience ratings. (A: RT Opposite/Sad, B: RT Opposite/Happy, C: RT Actual/Sad, D: Actual/Happy, E: Press/Sad, F: Press/Happy) Analyzing the effects of NCT-performances on the CECT performances. Concerning the NCT performances, the difference (e.g., delta) score was calculated between the first difficult version of the NCT and the post-pill administration easy version of the NCT, both for accuracy and response time. A Repeated Measures

52 44 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control GLM for Cue (opposite, actual, press) x Emotion (happy, sad) with Difference Scores as a covariate, showed no significant effects of the difference scores for reaction times (F(1, 20) = 0.015, p = 0.905), nor for the difference scores for accuracy (F(1,20) = 0.001, p = 0,980). Next we wanted to distinguish participants based on NCT performances before pill administration versus NCT performances after pill administration. Regarding reaction times we distinguished a group of 10 participant, who became slower on the first postpill easy NCT and a group of 12 participants who performed in a faster way during this first easy NCT version. In the remaining reports we will refer to this grouping as the NCT RT-groups. Both NCT RT-groups did not differ significantly on Age (F(1,20) = 2.137, p = 0.159) and Questionnaire Scores (Total STAI F(1, 20) = 1.880, p = 0.186, BDI F(1, 20) = 3.334, p = 0.083). As for accuracy level we distinguished a group of 10 participants who became more accurate and a group of 12 participants who performed less or in a similar way during the easy version of the NCT. These groups will be referred to as the NCT ACC-groups and did not differ significantly on Age (F(1, 20) = 0.109, p = 0.745) and Questionnaire Scores (Total STAI F(1, 20) = 0.607, p = 0.445; BDI F(1, 20) = 0.088, p = 0.770). Between the NCT RT-groups and NCT ACC-groups there was partial overlap. Next we performed a Repeated Measures GLM with measurements for the Cue (actual, opposite, press) x Emotion (happy, sad) trials as dependent variables and NCT RT-Group (slower/not slower NCT) as between subject factor. Results showed no between-subjects effects of NCT RT-grouping on reaction times for the cognitive control trials of the CECT (F(1, 20) = 0.796, p = 0.383). Similar findings were found for accuracy levels, with no significant effects of NCT RT-grouping on the accuracy levels of the CECT (F(1, 20) = 0.337, p = 0.568). Multivariate tests did reveal main effects for Cue and Emotion, both for reaction times and accuracy levels. Considering the NCT ACC-groups we performed a Cue (actual, opposite, press) x Emotion (Happy, Sad) by NCT ACC-Group (less accurate NCT/not) GLM. This analysis revealed no between-subject effects of NCT ACC-grouping on accuracy for the cognitive control trials of the CECT (F(1, 20) = 2.521, p = 0.128). Similarly, NCT ACC-grouping as between-subject factor had no significant effects on reaction times within the cognitive control trials (F(1, 20) = 0.008, p = 0.931).

53 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 45 Analyzing correlations between suggestibility measurements and mood. Additionally we examined bivariate correlations between our suggestibility measurements (NCT and control questionnaire) and positive or negative affect as measured by ratings on the PANAS. We found significant correlations between the positivity scores on the PANAS and ratings on the first question of the control questionnaire, probing the reliability and accurateness of the pharmacological and medical preparations (ρ = 0.504, p < 0.05). Also we found significant correlations between the negativity scores on the PANAS and the second (ρ = -0,494, p < 0.05) and third question of the control questionnaire (ρ = , p < 0.05). Besides we found significant correlations between negativity and reaction times during the two post-placebo NCT s, also appointed as the first (ρ = 0.463, p < 0.05) and second easy version (ρ = 0.450, p < 0.05) of the NCT. The correlation with the reaction times of the pre-placebo NCT was insignificant (ρ = 0.182, p = 0.417). ERP-Data Within the current dissertation, the available ERP-data is limited to the ones of the control group. ERP analyses were done by calculated spatio-temporal clusters. Figure x presents the grand average ERP waveforms, at electrode FCZ, for cues and target related activity. We performed a spatio-temporal cluster analysis with a time-window of 1500 msec. This way we encompass early to late ERP components generated in response to the cues. The analyses accounts for 93% of the variance.

54 46 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control Figure 5 Grand average ERP waveforms at electrode FCZ, separately for the cue (upper panels) and the target (lower panel). When visually inspecting the maps displayed in figure 5, we can perceive how early sensory cue processing (bilateral P1 and N1 occipital components) is followed by a clear-cut CNV component. This component is clearest at 1000 msec post-cue onset and sustains until 1500 msec after cue presentation. Moreover, the amplitude of the CNV component varied according to the presented cue. Specifically, paired t-tests showed that within the control group, the CNV had the largest amplitude for the press condition. Larger than either the actual (t(18) =2.80, p = 0.01) or opposite cue (t(18) = 2.31, p = 0.03), which didn t differ significantly. As for the target related ERP s, no systematic amplitude variation of the ERP signals was visible across the four main experimental conditions ( actual/happy, actual/sad, opposite/happy, opposite/sad interaction) (F < 0.7, p > 0.54).

55 The Influence of Placebo Cognitive Enhancing Drugs on Proactive and Reactive Cognitive Control 47 butterfly plot Figure 6 Grand average ERP data time-locked to the onset of the cue and shown using a standard Figure 6 shows the grand average ERP data during the press conditions. The presented amplitude is time-locked to the cue-onset. The vertical dashed line indicates the onset of the press cue. Discussion The goal of the present study was to manipulate the dual mechanisms of cognitive control during a CECT task, by modified interference expectancies, evoked via a specific placebo paradigm. Each trial of the CECT provides a cue, which allows participants to prepare or anticipate their response when the target appears. By influencing participants mindset in a way they expect less task interference, we expected them to adapt their cognitive control strategies. In particular we expected increased or decreased proactive control, counterbalanced by a decrease or increase in reactive control. We performed a pilot study in which we used solely verbal information to create placebo generating expectancies, but our placebo set-up appeared easy to see through. Therefore we decided to create the illusion of a double blind psychopharmacological experiment with informed consent, in which we tested the effects of a new cognitive stimulant. In addition we also implied a manipulated numeral comparison task, by which we aimed participants to