Memory enhancement with stimulants: Differential neural effects of methylphenidate, modafinil, and caffeine. A pilot study

Highlights

• Methylphenidate deactivated BOLD signal in fronto-parietal and temporal regions during recognition of previously learned words.

• Methylphenidate enhanced performance in late recall in a declarative memory task.

• Caffeine led to deactivations in the precentral gyrus during encoding.

• Modafinil did not show any BOLD signal alterations in a declarative memory task.

Abstract

Human memory is susceptible to manipulation in many respects. While consolidation is well known to be prone to disruption, there is also growing evidence for the enhancement of memory function. Beside cognitive strategies and mnemonic training, the use of stimulants may improve memory processing in healthy adults. In this single-dose, double-blind, within-subject, randomized, placebo-controlled pilot study, 20 mg methylphenidate (N = 13) or 200 mg modafinil (N = 12) or 200 mg caffeine (N = 14) were administrated to in total 39 healthy participants while performing a declarative memory task. Each participant received only one substance and functional magnetic resonance imaging (fMRI) was used to assess drug-dependent memory effects of the substance for encoding and recognition compared to task-related activation under placebo. While methylphenidate showed some behavioral effect regarding memory recall performance, on the neural level, methylphenidate-dependent deactivations were found in fronto-parietal and temporal regions during recognition of previously learned words. No BOLD alterations were seen during encoding. Caffeine led to deactivations in the precentral gyrus during encoding whereas modafinil did not show any BOLD signal alterations at all. These results should be interpreted with caution since this a pilot study with several limitations, most importantly the small number of participants per group. However, our main finding of task-related deactivations may point to a drug-dependent increase of efficiency in physiological response to memory processing.

Introduction

Declarative memory is part of the human memory system. The three stages of the memorization process, encoding, consolidation, and recall or recognition (Riedel & Blokland, 2015), have their neuronal representation in a network including the medial temporal lobe, prefrontal, and cortical regions (Borst and Anderson, 2013, Lisman and Grace, 2005, Scimeca and Badre, 2012, Squire et al., 2004). Thereby, catecholamines such as dopamine and noradrenaline seem to be crucial for the regulation of memory processing (Goldman-Rakic, 1995).

Memory consolidation, the process of long-term memory formation, further relies on a differential set of features such as pre-existing knowledge, as well as physiological and psychological function during learning (Squire, Genzel, Wixted, & Morris, 2015). Therefore, the consolidation of new memories is highly affected by the situational context, stress and arousal level (Kensinger and Corkin, 2003, Roozendaal and McGaugh, 2011). Thus, it can be assumed that consolidation of new information must be susceptible to manipulation in both directions: disruption and enhancement.

Noradrenaline and dopamine are the most frequently explored neurotransmitter with regard to memory enhancement (Riedel & Blokland, 2015). Several drugs that substantially affect the central dopamine system are thought to have enhancing properties, such as d-amphetamine, methylphenidate (MPH), tolcapone, and levodopa. Modafinil (MOD) as a dopamine and noradrenaline transporter inhibitor and, indirectly, caffeine (CAF) also influence central catecholamine metabolism (Ferré, 2016, Madras et al., 2006). However, drug dosage as well as characteristics of subjects and the examined cognitive domain of interest may interfere with the detection of performance effects (de Jongh, Bolt, Schermer, & Olivier, 2008). The investigated drugs of this study are further described below.

MPH is widely discussed as an enhancing drug (Compton et al., 2018, Repantis et al., 2010). Primarily prescribed for the treatment of attention-deficit/hyperactivity disorder (del Campo et al., 2013), MPH regulates catecholamine release in frontal-striatal pathways (Sharma & Couture, 2014). Animal studies on the effect of low-dose MPH show a positive effect on working memory (Arnsten and Dudley, 2005, Berridge et al., 2006), sustained attention (Andrzejewski et al., 2014), and long-term memory (Carmack, Block, Howell, & Anagnostaras, 2014). However, it is controversial whether MPH affects memory in healthy humans. While there are reports for positive MPH effects on working memory (Mehta et al., 2000), planning (Elliott et al., 1997) and memory function (Linssen, Sambeth, Vuurman, & Riedel, 2014), other studies could not identify significant effects of MPH on the recall of word lists (Hermens et al., 2007, Kuypers and Ramaekers, 2005). Other researchers have reported a baseline-dependent enhancing drug effect using a spatial association learning paradigm (I. C. Wagner, van Buuren, Bovy, Morris, & Fernandez, 2017). Depending on the cognitive task, MPH acts in a varied fashion in different brain regions in healthy adults (for a summary of published studies see Table S1). Until now, to our knowledge, no imaging study has focused on MPH effects on declarative memory in healthy individuals.

MOD is another stimulant that is supposingly being used as a cognitive enhancing substance (Repantis et al., 2010). Due to its wakefulness promoting properties it is approved for the treatment of narcolepsy (Dauvilliers, Billiard, & Montplaisir, 2003). MOD elevates extracellular catecholamine levels and activates indirectly the hypocretinergic system. It predominantly affects cortical areas of the frontal lobe and shows minor activity in subcortical sites (Minzenberg & Carter, 2008). Reports from animal studies exploring the effect of MOD are inconsistent (Wood, Sage, Shuman, & Anagnostaras, 2014). Memory processes specifically are enhanced in a very selective and dose-dependent fashion (Shuman, Wood, & Anagnostaras, 2009). In humans, a systematic review of sleep-deprivation studies suggests that MOD helped healthy individuals to maintain wakefulness, memory, and executive functions to a higher degree than placebo after one night of sleep deprivation (Battleday & Brem, 2015). The data for non-sleep deprived individuals are less clear. Among many null effect studies, some studies suggest that MOD could act as a cognitive enhancer in the domains of attention (Baranski et al., 2004, Makris et al., 2007) and memory processing (Müller et al., 2013, Randall et al., 2005). Of note, MOD’s mode of action shows a diverse, task-dependent pattern (see Table S2). Up to now, no imaging studies on MOD’s effect on verbal memory have been performed.

CAF is a natural stimulant occurring in several plants and commonly consumed in coffee, tea and soft drinks. In addition, it is discussed as an off-label treatment in several neurological disorders (Rivera-Oliver & Diaz-Rios, 2014). Besides its peripheral effects, CAF acts as a non-selective adenosine receptor antagonist (Takahashi, Pamplona, & Prediger, 2008) through which an upregulation of dopamine signaling in the putamen and ventral striatum is being achieved (Volkow et al., 2015). This mechanism may account for the increased arousal, locomotor behavior, and stimulation after CAF intake (Ullrich et al., 2015). These enhancing effects become more pronounced when individuals are sleep-deprived or lowered in alertness before CAF consumption (Smith, 2002). Summarizing previous data on the effects of CAF on cognition, Nehlig (2010) reported positive effects on working memory, mood and concentration, but not verbal memory function (Nehlig, 2010). In a study in which a single-dose was given after learning, Borota and colleagues (2014) found positive effects on memory consolidation but not on retrieval (Borota et al., 2014). This suggests that time of intake also influences the potential memory enhancing effect of CAF. Furthermore, Hameleers and colleagues (2000) reported positive effects of habitual CAF consumption on long-term memory whereas no effect on other cognitive functions was found (Hameleers et al., 2000). There are only a few studies using a demanding cognitive paradigm during imaging after CAF administration (see Table S3). Two fMRI studies on working memory in young healthy adults (Klaassen et al., 2013, Koppelstaetter et al., 2008) showed that CAF activates a fronto-parietal network, which also plays a key role in attention and memory retrieval (Fox et al., 2005).

By employing a double-blind, within-subject design alternating placebo and single-drug administration, the effect of three different stimulants (MPH, MOD, CAF) on memory performance in encoding, recognition, early and late recall was investigated. The behavioral results were already reported elsewhere (Repantis, Bovy, Ohla, Kuhn, & Dresler, 2021). Briefly, domain-specific and moderate effects were seen for MPH and CAF while no significant effect was seen for MOD in any assessment of the test battery. MPH slightly improved self-reported fatigue and late recall 24 h after learning, but not memory recognition nor immediate recall after learning word lists of a declarative memory task. After CAF intake, sustained attention was significantly improved. Here we report the results of functional imaging during task performance, which was used in order to investigate drug-induced changes of MPH, MOD and CAF on the neural level, expecting changes in brain function in the memory-associated brain areas that were discussed above.