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No Role of Beta Receptors in Cognitive Flexibility: Evidence from a Task-Switching Paradigm in a Randomized Controlled Trial

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No Role of Beta Receptors in Cognitive Flexibility: Evidence from a Task-Switching Paradigm in a Randomized Controlled Trial Neuroscience 295 (2015) 237–242 NO ROLE OF BETA RECEPTORS IN COGNITIVE FLEXIBILITY: EVIDENCE FROM A TASK-SWITCHING PARADIGM IN A RANDOMIZED CONTROLLED TRIAL L. STEENBERGEN, * R. SELLARO, M. DE ROVER, in an attentional set-shifting task (Lapiz and Morilak, B. HOMMEL AND L. S. COLZATO 2006). Comparable improvements in set shifting have Institute for Psychological Research, Leiden University, Leiden, been achieved by chronic treatment with desipramine, The Netherlands an NE-reuptake blocker, and atipamezole, an a-2-adre- Leiden Institute for Brain and Cognition, Leiden University, nergic autoreceptor antagonist (Lapiz et al., 2007; Bondi Leiden, The Netherlands et al., 2010). Moreover, lesions of the dorsal noradrenergic bundle created by 6-hydroxydopamine, which causes sub- stantial depletions of cortical NE, seem to selectively Abstract—There is evidence that noradrenergic coeruleo- impair set shifting (Tait et al., 2007). Last, specific decre- cortical projections are involved in different forms of cogni- ments in attentional set-shifting task were obtained in rats tive flexibility. So far, no studies in humans have investigated after noradrenergic but not cholinergic deafferentiation the involvement of beta receptors on task-switching perfor- mance, a well-established measure of cognitive flexibility. (McGaughy et al., 2008). In humans, NE reuptake inhibi- The present study investigated whether the administration tors, such as atomoxetine, have been suggested as poten- of propranolol (a central and peripheral beta-adrenergic tial cognitive enhancers in schizophrenia because of their antagonist) affected switching costs (i.e., the increase of capacity to indirectly but selectively increase extracellular reaction time in task-switching trials relative to task- dopamine concentrations in the prefrontal cortex repetition trials). Sixteen healthy adult human subjects (Friedman et al., 2004). Moreover, propranolol (a central performed a global–local task-switching paradigm in a and peripheral b-adrenergic antagonist) and nadolol double-blind, within-subjects design study investigating (peripheral b-adrenergic antagonist) have been found to the effects of 80 mg of propranolol hydrochloride (a b1 and modulate mean time-to-solution in insight problem-solv- b2 adrenergic receptor antagonist) vs. an oral dose of micro- ing, a function related to cognitive flexibility (Beversdorf crystalline cellulose (placebo pill). The acute administra- tion of propranolol did not affect the size of switching costs et al., 1999, 2002; Campbell et al., 2008). compared to the intake of the neutral placebo. Our results, The goal of the present study was to examine in corroborated by Bayesian inference, suggest that beta humans whether cognitive flexibility can be modulated receptors do not modulate cognitive flexibility as measured by NE using task switching performance, a reliable by task-switching performance. Ó 2015 IBRO. Published by indicator of cognitive flexibility (Miyake et al., 2000; Elsevier Ltd. All rights reserved. Monsell, 2003). The total time to switch between two dif- ferent tasks (i.e., switching costs) can be taken to reflect the efficiency of adapting and restructuring cognitive representations, so that smaller switching costs indicate Key words: norepinephrine, beta receptors, cognitive a higher degree of cognitive flexibility. In this type of flexibility, task-switching. paradigm, the sequence of tasks is often predictable and consistent (e.g., AABBAABB...). Therefore, partici- pants know when to prepare for a task switch, so that INTRODUCTION the interval between the previous response and the The animal literature suggests that various forms of upcoming stimulus (the response–stimulus interval or cognitive flexibility, such as shifting attention between RSI) can be considered a preparation interval. In switch perceptual dimensions, are mediated by the activity of trials, participants can use this preparation interval to the locus coeruleus (LC)–norepinephrine (NE) system reconfigure their cognitive task set. (see Robbins and Arnsten, 2009, for a review). In rats, Given that propranolol has been found to modulate augmenting noradrenergic activity at a-1-receptors in the insight problem-solving (Beversdorf et al., 1999, 2002; medial prefrontal cortex promotes cognitive performance Campbell et al., 2008), a function related to cognitive flexi- bility, in the present study we investigated whether the administration of propranolol affects the size of switching *Correspondence to: L. Steenbergen, Institute for Psychological Research, Leiden University, Cognitive Psychology Unit, Wasse- costs. Based on the evidence suggesting a pivotal role of naarseweg 52, 2333 AK Leiden, The Netherlands. NE in driving cognitive flexibility (Robbins and Arnsten, E-mail address: [email protected] (L. Steenbergen). 2009), we predicted larger switching costs after propra- Abbreviations: H0, null hypothesis; LC, locus coeruleus; ms, miliseconds; NE, norepinephrine. nolol intake than after the intake of a neutral placebo. http://dx.doi.org/10.1016/j.neuroscience.2015.03.049 0306-4522/Ó 2015 IBRO. Published by Elsevier Ltd. All rights reserved. 237 238 L. Steenbergen et al. / Neuroscience 295 (2015) 237–242 EXPERIMENTAL PROCEDURES were made by pressing the ‘‘Z’’ or ‘‘/’’ of the QWERTY computer keyboard with the left and right index fingers, Participants respectively. The target stimuli were adopted from Sixteen healthy native Dutch-speaking subjects [eight Colzato et al. (2010) and Christoffels et al. (2014) and male, mean age (SD) = 24.3 (3.5); eight female, mean consisted of geometric figures. Larger (global) rectan- age = 22.6 (3.4)] took part in our studies in return for gles/squares consisted of smaller (local) rectangles or 100 Euros. Only participants with a systolic blood squares. Global stimuli (i.e., squares or rectangles; pressure above 100 mmHg, a diastolic blood pressure 93 Â 93 pixels or 41 Â 189 pixels respectively) were com- above 60 mmHg and a resting heart rate above 60 beats posed of many smaller ‘‘local’’ stimuli (i.e., squares or rec- per minute were included in the study. All volunteers tangles; 21 Â 21 pixels or 8 Â 46 pixels respectively). The gave written informed consent. Participants were space between the local elements of a stimulus was 3 pix- screened to be free of neurological, psychiatric and els. A global square consisted of 16 small squares or 16 physical illness and had not been on any medication for small rectangles; a global rectangle consisted of 16 small at least 3 months. All subjects were medically screened squares or 16 small rectangles. The ‘‘local’’ and ‘‘global’’ and considered to be in satisfactory health. Subjects cues were the same size as the global and local stimuli received an oral dose of 80 mg of propranolol and were presented at 189 pixels from the center of the hydrochloride (a b1 and b2 adrenergic receptor computer screen. antagonist) or 80 mg of cellulose microcrystalline Participants were presented with one of the four (placebo pill) in a double-blind, randomized and counter- possible stimuli: a rectangle consisting of smaller balanced, within-subjects design. Propranolol and rectangles or squares, or a square consisting of smaller placebo were administered to each participant on rectangles or squares. A cue (a rectangle and square, consecutive days (24 h in between administrations). congruous in location with the associated response Drug allocation was balanced for gender. Heart rate, and button) appeared 400–600 miliseconds (ms) before the systolic and diastolic blood pressure were measured stimulus (located at the center of the screen, between immediately before drug administration (time 0 min) and the two cues). The cue was either small or large, and at the beginning (time + 205 min) and end of the task- indicated to which level (global/local) the participants switching paradigm (time + 230 min). One subject was should attend in the upcoming stimulus (see Fig. 1). excluded from the study because of the severe side The rectangle or square was associated with a spatially effects (cardiorespiratory arrest) after propranolol assigned response button that was pressed with either ingestion (de Rover et al., 2010, see also de Rover et al., the left (‘‘Z’’ from a QWERTY keyboard) or right (‘‘/’’ 2012). Data of one other additional participant were omit- from a QWERTY keyboard) index finger. Which ted, as he committed more than 30% of errors performing stimulus corresponded to which button was the task-switching paradigm. The study was approved by counterbalanced across participants. The four possible the medical ethics committee of the Leiden University stimuli made that trials could either be congruent or Medical Center and was conducted according to the incongruent. A congruent trial was a bigger shape built Declaration of Helsinki. up out of similar smaller shapes (e.g., a large square consisting of smaller squares), an incongruent trial a bigger shape built up out of different smaller shapes Procedure (e.g., a large square consisting of smaller rectangles). Each subject was tested at approximately the same time Both the color of cues and the color of the target of the day (noon). Subjects were instructed to abstain stimulus were red, and both remained on the screen from alcohol, but also caffeine, nicotine, and other until a response was given or 2500 ms had passed. The psycho-active substances from 15 h before the start of interval between response and presentation of the next the session until the day after
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