The effects of methylphenidate and propranolol on the interplay between induced-anxiety and working memory

Abstract

Rationale: Research documents a reciprocal impact of anxiety on working memory (WM), although its strength and direction depend on factors like task difficulty. A better understanding of these factors may generate insights into cognitive mechanisms of action involved in anxiety, culminating into treatment implications. By blocking the physiological effects of anxiety, propranolol might also block anxiety interference on WM. Conversely, by improving task-directed attention, methylphenidate might reduce anxiety, or, alternatively, by improving cognitive efficiency and free up processing resources to compute anxiety.

Objectives: To investigate the interplay between induced anxiety and WM, we pharmacologically manipulated either anxiety or cognition, using single doses of 40 mg propranolol (PRO), 20 mg methylphenidate (MPH), or placebo (PLA). In this double-blind parallel-group design study, 60 healthy volunteers (20/drug group) performed a verbal WM task under three loads, 1-, 2- and 3-back, and in two conditions, threat of shock and safety. Startle electromyography (EMG) was used to measure anxiety.

Results: Findings were twofold: (1) MPH blocked anxiety interference only on the 3-back WM performance, while PRO or PLA had no effects on anxiety-WM interference, and (2) drugs had no effects on anxiety, but, after controlling for baseline anxiety, MPH enhanced anxiety-potentiated startle during the 3-back task.

Conclusions: These findings support that MPH-related improvement of cognitive efficiency permits anxiety to be processed and expressed. In conclusion, MPH may be a useful tool to investigate the mechanisms of interaction between anxiety and WM, particularly those under catecholaminergic control.

Keywords: Catecholamine; Cognition; Dopamine; Fear-potentiated startle; Limited resources theory; Stimulant.

Fig. 1

Schematic of the WM task. a) Illustration of a run. There were two conditions, threat and safe. Subjects were informed that under the threat condition, they could receive electric shocks at any time (illustrated here as yellow lightning bolts), while during the safe condition they would not receive shocks. A total of eight shocks (2 per run; 0 or 2 per threat block) were delivered during the task. To minimize sensitization effects of the shocks on startle, shocks preceded startle probes (represented here as black diamonds) by at least 16 s and followed startle probes with a mean latency of approximately 2 s. b) Illustration of a 1-back WM block. One-back blocks occurred during each threat and safe condition. Both uppercase and lowercase letters (18 in each block) were presented to reduce reliance on perceptual information. Letters were shown for 500 ms each, separated by 2000 ms intertrial intervals (ITIs). Subjects were asked to indicate on a keyboard whether each letter was the same (“s”) or different (“d”) from the letter they had just seen (1 letter back). For the 2-back, subjects compared the letter to the one they had seen 2 letters prior, and for the 3-back, the one they had seen 3 letters prior. For all levels, approximately 35 % of letters were targets (i.e., “same” responses). (Color figure online)

Fig. 2

Accuracy during threat and safe conditions. Drug condition affected accuracy only at the level of highest difficulty of the working memory task (load-3). The y-axis shows percent accuracy. The working memory task (n-back) was performed at easy (load-1), medium (load-2), and hard levels (load-3). There was a significant difference among drug groups (placebo vs. propranolol vs. methylphenidate) only at the hard level (load-3), when the methylphenidate group was the only group failing to show a threat-induced impairment in accuracy. PLA placebo, PRO propranolol, MPH methylphenidate

Fig. 3

Reaction time during threat and safe conditions. Drug condition affected reaction time in the placebo and propranolol, but not methylphenidate, groups. The y-axis shows reaction time (ms), and the x-axis shows drug groups clustered by working memory task (n-back) difficulty: easy (load-1), medium (load-2), and hard (load-3). In the placebo and propranolol groups, threat increased reaction time in the easy level, or low load, but shortened reaction time in the hard level, or high load. Threat did not modulate reaction time in the methylphenidate group. PLA placebo, PRO propranolol, MPH methylphenidate

Fig. 4

Threat-induced changes in startle (anxiety-potentiated startle). Mean and standard error of the [threat minus safe] differences of startle EMG z-scores (anxiety-potentiated startle). The three-way rANOVA of group × condition × load failed to show any effects of drug, either as a main effect or an interaction. However, the examination of load-3 using a two-way rANOVA revealed a trend for a significant condition × drug interaction (F_(2,56) = 3.0, p = 0.06). This interaction was due to the strongest anxiety-potentiated startle response in the MPH group, and weakest in the PRO group