The Neurocognitive Cost of Enhancing Cognition with - IA de Investigación especializada en el MIT

El costo neurocognitivo de mejorar la cognición con
Methylphenidate: Improved Distractor Resistance but
Impaired Updating

Sean James Fallon1,3, Marieke E. van der Schaaf1,2, Niels ter Huurne2, and Roshan Cools1,2

Abstracto

■ A balance has to be struck between supporting distractor-
resistant representations in working memory and allowing those
representations to be updated. Catecholamine, particularly dopa-
mío, transmission has been proposed to modulate the balance
between the stability and flexibility of working memory represen-
taciones. Sin embargo, it is unclear whether drugs that increase cate-
cholamine transmission, such as methylphenidate, optimize this
balance in a task-dependent manner or bias the system toward
stability at the expense of flexibility (or vice versa). Here we dem-
onstrate, using pharmacological fMRI, that methylphenidate im-
proves the ability to resist distraction (cognitive stability) pero

impairs the ability to flexibly update items currently held in work-
ing memory (flexibilidad cognitiva). These behavioral effects were
accompanied by task-general effects in the striatum and opposite
and task-specific effects on neural signal in the pFC. This suggests
that methylphenidate exerts its cognitive enhancing and impair-
ing effects through acting on the pFC, an effect likely associated
with methylphenidate’s action on the striatum. Estos hallazgos
highlight that methylphenidate acts as a double-edged sword,
improving one cognitive function at the expense of another,
while also elucidating the neurocognitive mechanisms underlying
these paradoxical effects. ■

INTRODUCCIÓN

Methylphenidate is used to treat attention deficit hyper-
activity disorder (TDAH; Swanson et al., 1998) and is also
taken by healthy adults in the hope of improving aca-
demic and cognitive performance (Maher, 2008). Methyl-
phenidate acts by blocking the dopamine transporter
(Gatley et al., 1999; Ritz, Lamb, Goldberg, & Kuhar,
1987), leading to increased dopamine and noradrenaline
in pFC (Berridge et al., 2006) and increased dopamine in
striatal areas ( Volkow et al., 2001).

Despite the widespread use of methylphenidate, char-
acterizing its precise cognitive effects has proved to be a
difficult task. Por ejemplo, despite the well-known
dependence of working memory on catecholaminergic
tono (Berridge & Arnsten, 2013; Vijayraghavan, Wang,
Birnbaum, williams, & Arnsten, 2007; Zahrt, taylor,
Mathew, & Arnsten, 1997; Brozoski, Marrón, Rosvold, &
hombre de oro, 1979), the effects of methylphenidate on work-
ing memory are variable (Ilieva, Hook, & Farah, 2015;
Herrero & Farah, 2011). Some of this variability likely reflects
individual differences in dopamine release (Clatworthy
et al., 2009). Sin embargo, the precise nature of the task de-
mands is now also known to contribute to the direction

1Radboud University Donders Institute of Brain, Cognición, y
Comportamiento, 2Radboud University Nijmegen Medical Centre,
3Universidad de Oxford

and extent of catecholaminergic drug effects (Caer sobre
et al., 2015; Linssen, Sambeth, Vuurman, & Riedel, 2014;
Barí & robbins, 2013; Floresco, 2013; Mehta, Manes,
Magnolfi, Sahakian, & robbins, 2004; Cools, Pregonero, Sahakian,
& robbins, 2001; Gotham, Marrón, & Marsden, 1988).

Although much research on working memory focuses
on delay-related stabilization of memoranda, it is widely
recognized that attentional mechanisms—the gating and
selection of specific stimuli—play an integral part in de-
termining the life span and vivacity of remembered items
(Caer sobre, Zokaei, & Husain, 2016; Gazzaley & Nobre,
2012). A balance has to be struck between supporting
robust mental representations that are resistant to inter-
ference (cognitive stability) and allowing those represen-
tations to be sufficiently flexible to be updated (cognitivo
flexibilidad; Más valiente & cohen, 2000). De este modo, although it may
be advantageous in certain contexts to keep hold of infor-
mation and protect it from distraction, it is also important
to efficiently update information that is no longer rele-
vant. Sin embargo, the extent to which gating the entry of
items into working memory is affected by changes in cat-
echolaminergic tone and the neural locus of these effects
have not been examined. According to existing neuro-
computational models, methylphenidate, through modu-
lating dopamine levels, might have antagonistic effects
on the stability versus flexibility of mnemonic repre-
sentaciones (Durstewitz & Seamans, 2008; Hazy, Franco,
& O’Reilly, 2007), an idea that runs counter to its clinical

Revista de neurociencia cognitiva 29:4, páginas. 652–663
doi:10.1162/jocn_a_01065

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usage, and the suggestion that methylphenidate acts as a
uniform cognitive enhancer.

The neural locus of any differential effect on stability ver-
sus flexibility is hotly contested. Dopamine has been hypoth-
esized to modulate the balance between cognitive stability
and flexibility through acting on the pFC (Durstewitz &
Seamans, 2008), the striatum (Hazy et al., 2007), or through
there being a division of labor, with the frontal cortex pro-
moting stability and the striatum promoting flexibility
(Cools & D'Esposito, 2011). In particular the dorsal stria-
tum, and its modulation by dopamine, has been implicated
in updating (or preparing to update) items in working
memory (Caer sobre & Cools, 2014; Yu, FitzGerald, & Friston,
2013; Murty et al., 2011; Dahlin, Neely, Larsson, Backman,
& Nyberg, 2008; Hazy et al., 2007). This study sought to ad-
judicate between these hypotheses by examining whether
any effect of methylphenidate on the tradeoff between cog-
nitive stability and flexibility is accompanied by neural
changes in the frontal cortex and/or dorsal striatum using
pharmacological fMRI.

Although methylphenidate is assumed to act on cogni-
tive functions directly, there is another possibility: Meth-
ylphenidate may exert its effects on working memory
vicariously, via boosting the response to rewarding
events that subsequently alter the mnemonic functions
of the pFC. This hypothesis concurs generally with recent
observations that working memory allocation is value-
based (Chatham & malo, 2013; Dayán, 2012; dixon &
cristóbal, 2012; Hazy et al., 2007). More directly, previ-
ously we have found that the reward-related BOLD signal
increase in the ventral striatum for an unexpected finan-
cial gain, compared with a loss, predicted its effect on
ignoring or updating items in working memory (Caer sobre
& Cools, 2014). Given that reward-related processing
in the ventral striatum is thought to be dopaminergic in

origen (Knutson & Gibbs, 2007), methylphenidate might
modify the ventral striatal response to gains versus losses,
which in turn exerts downstream effects on cognitive
control. De este modo, we also assessed the hypothesis that meth-
ylphenidate affects cognitive control vicariously through
modulating ventral striatal reward response.

Using pharmacological fMRI, we examined the effect of
methylphenidate on a modified delay match-to-sample
task in a double-blind placebo-controlled crossover
estudiar. The task was modified to include two additional
phases during the delay period between encoding and
probe (Cifra 1). Primero, participants received an unexpected
outcome (gain, neutral, or loss) after playing a gamble.
Next they were presented with novel intervening stimuli,
which had to be either ignored or updated in working
memory.

MÉTODOS

Participantes

Twenty-four participants (11 hombres, 13 women) gave writ-
ten informed consent to take part in this study and were
compensated for participation (A130). Three partici-
pants were excluded (two due to incomplete data due
to scanner malfunction and one due to inability to per-
form task in the scanner; mean accuracy ∼38%). The re-
maining participants were aged between 19 y 28 años
(mean = 21.40 años).

Inclusion and Exclusion Criteria

Exclusion criteria for participation in the study were as
follows: uncorrected visual impairment (p.ej., color
blindness), history of neurological or psychiatric disorder,

Cifra 1. An illustration of the
modified delay match-to-sample
task used (Caer sobre & Cools,
2014). Los participantes fueron
presented with two stimuli
that always had to be encoded
(2000 mseg). After a variable
delay period (2000–6000 msec),
a 1500-msec response screen
requested participants to make
a choice to receive a gain,
neutral, or loss outcome
(1000 mseg). After another
variable delay period (2000–
6000 mseg), participants were
presented with novel stimuli
(1000 mseg) that had to be
ignored or used for working
memory updating (displacing
the original targets). A no-interference condition, in which only a fixation cross appeared (1000 mseg), was included as a control condition. Después
another variable delay period (2000–6000 msec), participants were presented with a probe item. Participants had to responding according to whether
the presented item matched or did not match one of those items in the same. In the present example, the correct answer would be a match
if the current trial was in the ignore or no-interference condition, but a nonmatch in the update condition. They had a maximum of 2000 mseg
to respond.

Fallon et al.

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history of medical treatment to head or neck, history of
asthma, history of disorder that may affect metabolism or
circulation (diabetes, hypertension, cardiac arrhythmia),
currently taking over-the-counter medications, el embarazo,
metallic implants, current smoker, consumption of >20
units alcohol or 20 cigarettes per week, history of hard drug
usar (p.ej., heroin or cocaine), cannabis use <2 weeks before testing and history, left-handedness, tattoos, unremovable body piercings, claustrophobia, frequent gambling (e.g., casino, fruit machines). Intake Testing Procedures Participants took part in an intake session, during which they performed some baseline tests were trained on the tasks that they had to perform on each of the test days. Participants screened by a medical doctor (NtH) check for contraindications taking methyl- phenidate (family history tics, etc.) screened by psychologist (MvdS) using Mini International Neuropsychiatric Interview (Sheehan et al., 1998) to assess any psychiatric problems. Physiological measurements (height, weight, pulse rate, blood pressure) following psychological measures were also assessed: depression (Beck Depression Inven- tory; Beck, Ward, Mendelson, Mock, & Erbaugh, 1961), trait anxiety (Spielberger Trait Anxiety Inventory; Spielberger, Gorsuch, Lushene, 1970), ADHD symptomatology (Pappas, 2006). Pharmacological Design Procedure Participants tested within-subject, double- blind, placebo-controlled cross-over design two sepa- rate occasions, once after 20 mg methylphenidate (Ritalin) placebo substance, with the order counterbalanced across participants. This dose was chosen as it has been found exert cognitive effects (Elliott 1997; though see Linssen 2011). The drug sessions occurred with minimum a 1-week gap maximum 4-week gap. Scanning took place roughly 1 hr drug administration. Task Procedure The task is modified delay match-to-sample and has fully described (Fallon Cools, 2014; Figure 1). Each trial contained four distinct phases separated by three periods. Encoding Phase Participants presented letter “T” the middle screen flanked computer-generated “spirographs” different colors. Note every shape was novel color (RGB value). The presence center indicated that stimuli be remembered “Target” stimuli. Outcome Phase On gain loss trials, participants guess the outcome coin toss making head or tails response with their index middle finger, respectively. Two screens were then presented: “LOSS” negative au- ditory tone (“horn”; A1); “WIN” a positive auditory (cash register; win A1). Gains and losses did not depend performance, equally frequent, lead net>
The Neurocognitive Cost of Enhancing Cognition with image

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