ArticlePDF AvailableLiterature Review

Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review

September 2015
European Neuropsychopharmacology 25(11)

September 2015
25(11)

DOI:10.1016/j.euroneuro.2015.07.028

Authors:

Ruairidh McLennan Battleday

Princeton University

Anna-Katharine Brem

University of Bern and King's College London

Modafinil is an FDA-approved eugeroic that directly increases cortical catecholamine levels, indirectly upregulates cerebral serotonin, glutamate, orexin, and histamine levels, and indirectly decreases cerebral gamma-amino-butrytic acid levels. In addition to its approved use treating excessive somnolence, modafinil is thought to be used widely off-prescription for cognitive enhancement. However, despite this popularity, there has been little consensus on the extent and nature of the cognitive effects of modafinil in healthy, non-sleep-deprived humans. This problem is compounded by methodological discrepancies within the literature, and reliance on psychometric tests designed to detect cognitive effects in ill rather than healthy populations. In order to provide an up-to-date systematic evaluation that addresses these concerns, we searched MEDLINE with the terms "modafinil" and "cognitive", and reviewed all resultant primary studies in English from January 1990 until December 2014 investigating the cognitive actions of modafinil in healthy non-sleep-deprived humans. We found that whilst most studies employing basic testing paradigms show that modafinil intake enhances executive function, only half show improvements in attention and learning and memory, and a few even report impairments in divergent creative thinking. In contrast, when more complex assessments are used, modafinil appears to consistently engender enhancement of attention, executive functions, and learning. Importantly, we did not observe any preponderances for side effects or mood changes. Finally, in light of the methodological discrepancies encountered within this literature, we conclude with a series of recommendations on how to optimally detect valid, robust, and consistent effects in healthy populations that should aid future assessment of neuroenhancement.

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REVIEW

Modaﬁnil for cognitive neuroenhancement

in healthy non-sleep-deprived

subjects: A systematic review

R.M. Battleday

, A.-K. Brem

a,b

Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom

Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of

Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

Received 29 January 2015; received in revised form 27 July 2015; accepted 30 July 2015

KEYWORDS

Neuroenhancement;

Modaﬁnil;

Cognitive;

Psychometric;

Enhancement;

Nootropic

Abstract

Modaﬁnil is an FDA-approved eugeroic that directly increases cortical catecholamine levels, indirectly

upregulates cerebral serotonin, glutamate, orexin, and histamine levels, and indirectly decreases

cerebral gamma-amino-butrytic acid levels. In addition to its approved use treating excessive

somnolence, modaﬁnil is thought to be used widely off-prescription for cognitive enhancement.

However, despite this popularity, there has been little consensus on the extent and nature of the

cognitive effects of modaﬁnil in healthy, non-sleep-deprived humans. This problem is compounded by

methodological discrepancies within the literature, and reliance on psychometric tests designed to

detect cognitive effects in ill rather than healthy populations. In order to provide an up-to-date

systematic evaluation that addresses these concerns, we searched MEDLINE with the terms “modaﬁnil”

and “cognitive”, and reviewed all resultant primary studies in English from January 1990 until

December 2014 investigating the cognitive actions of modaﬁnil in healthy non-sleep-deprived humans.

We found that whilst most studies employing basic testing paradigms show that modaﬁnil intake

enhances executive function, only half show improvements in attention and learning and memory, and

a few even report impairments in divergent creative thinking. In contrast, when more complex

assessments are used, modaﬁnil appears to consistently engender enhancement of attention, executive

functions, and learning. Importantly, we did not observe any preponderances for side effects or mood

changes. Finally, in light of the methodological discrepancies encountered within this literature, we

conclude with a series of recommendations on how to optimally detect valid, robust, and consistent

effects in healthy populations that should aid future assessment of neuroenhancement.

www.elsevier.com/locate/euroneuro

http://dx.doi.org/10.1016/j.euroneuro.2015.07.028

Correspondence to: Helen Wills Neuroscience Institute, 175 Li Ka Shing Center MC#3370, UC Berkeley, Berkeley, CA 94720, USA.

E-mail address: ruairidh.battleday@gmail.com (R.M. Battleday).

European Neuropsychopharmacology (2015) 25, 1865–1881

1. Introduction

“Neuroenhancement”refers to the targeted enhancement and

extension of cognitive and affective abilities based on an

understanding of their underlying neurobiology, and is increas-

ingly represented by the media as an eventuality, usually in a

desirable context. In reality, most contemporary strategies for

neuroenhancement –comprising invasive and non-invasive brain

stimulation and pharmacological manipulation –remain in their

infancy. However, one agent, the FDA-approved eugeroic

modaﬁnil, has been extensively evaluated for cognitive mod-

ulation in healthy humans, and appears safe for widespread

use. Unfortunately, discrepancies in methodology and outcomes

within the literature have precluded consensus on the nature

anddegreeofmodaﬁnil's effects on cognition, and continue to

undermine discussions on the suitability of its off-label use as a

cognitive enhancer, which is already thought to be extensive

(Franke et al., 2013;Maher, 2008). In particular, studies using

simple psychometric assessments derived from assessments of

animal cognition or clinical populations have tended to report

variable outcomes following modaﬁnil intake (see, for example,

Randall et al. (2003,2004,2005a,2005b)), whereas more

recent studies using complex testing paradigms have tended to

report beneﬁcial effects (see, for example, Finke et al. (2010)).

Thus,weaimtoprovideanevaluationofmodaﬁnil as a

neuroenhancement agent that addresses these discrepancies.

To d o s o , w e ﬁrst introduce modaﬁnil's molecular actions in the

context of its pharmacological contemporaries, as well as the

basic psychometric tests commonly employed to detect any

alteration of cognition by these agents, before reporting the

results of a systematic review on the cognitive effects of

modaﬁnil. We then follow this with methodological criticism

of study designs employed to date, and offer a set of criteria

that builds these observations into guidance for future study of

neuroenhancement.

1.1. Modaﬁnil and other pharmacological

neuroenhancement agents

Pharmacological neuroenhancement agents may target online

cognitive processes, such as attention and executive function,

ofﬂine processes, such as memory consolidation, or a combina-

tion of the two. The stimulant methylphenidate (Ritalin

which increases central catecholamine levels, appears to

mainly target online processes, with some studies observing

improvements in working memory, speed of processing, verbal

learning and memory, and various attentional functions includ-

ing vigilance (see Linssen et al. (2014);butseeRepantis et al.

(2010)). Despite the extensive attention that methylphenidate

has received for cognitive enhancement, the signiﬁcant side

effect proﬁle and high abuse potential that accompanies its use

have curtailed discussions about wider societal use (Linssen

et al., 2014). Conversely, piracetam, a racetam drug that

may ameliorate cognitive decline in clinical populations

(Waegemans et al., 2002), appears to target ofﬂine properties

via modulation of acetylcholinergic and glutamatergic systems

and increases in membrane permeability (Winblad, 2006), but

appears to have limited effects in healthy humans (Dimond and

Brouwers, 1976;Mindus et al., 1976). In addition, several

herbal substances –namely Panax ginseng,Ginkgo biloba,and

Bacopa monneri, all of which contain a mixture of neuroactive

compounds attributed with pleiotropic molecular and cognitive

effects –have been investigated for their potentiation of both

online and ofﬂine processes (Aguiar and Borowski, 2013;

Farooqui, 2012;Lü et al., 2009;Neale et al., 2013). However,

methodological and evidential inconsistency within this corpus

of research has obviated the demonstration of any robust

effects on cognition.

Modaﬁnil shares features with all of these agents: it is a

stimulant drug, like methylphenidate; and, like the herbal

substances and piracetam, exerts a complex neurochemical

proﬁle affecting both online and ofﬂine processes. Modaﬁnil

was ﬁrst marketed in France in the 1990s as a eugeroic

treatment for narcolepsy, and has since been FDA-approved

for the treatment of excessive somnolence in narcolepsy,

obstructive sleep apnoea, and shift work sleep disorder

(Kumar, 2008). Modaﬁnil directly inhibits central dopamine

and noradrenaline uptake transporters, causing an elevation

in catecholamine levels (Qu et al., 2008); these effects in

turn elevate extracellular concentrations of serotonin, glu-

tamate, histamine, and orexin, and reduce concentrations of

gamma-amino-butrytic acid. Arousal- and wakefulness-

promoting actions are thought to arise from these increases

in dopaminergic and adrenergic transmission, and interac-

tions with the orexin/hypocretin axis (Minzenberg and Carter,

2008). Although modaﬁnil effects are thought to arise

primarily from alterations in cortical neurotransmitter sys-

tems, similar neurochemical modulations have been reported

in the hippocampus, thalamus, hypothalamus, amygdala,

caudate, and midbrain (see Scoriels et al. (2013)).

1.2. Imaging studies

Modaﬁnil does not appear to diffusely increase cortical

activation (Ellis et al., 1999); rather, selective brain net-

works and inter-areal functional connectivity are altered.

Resting-state imaging studies have shown that modaﬁnil

intake increases regional blood ﬂow in bilateral precentral

gyri, left hippocampus, left fusiform gyrus, bilateral lingual

gyri, and cerebellum in narcoleptic and healthy participants

(Joo et al., 2008). When Esposito and colleagues examined

the activity of seven resting-state cortical networks, they

found that in the absence of structural changes modaﬁnil

intake increases activity in the Dorsal Attention Network –

thought to modulate externally-directed attention by

amplifying or attenuating the saliency of relevant and

irrelevant cues –and increased connectivity in the anterior

cingulate cortex (ACC) node of the left Frontal Parietal

Control network (Esposito et al., 2013)–which may mediate

planning across domains (Spreng et al., 2010). On further

analysis, this group found that although overall activity in

the Saliency Network –which orients attention towards key

environmental stimuli and helps guide behaviour –was

unchanged, functional coupling between the right posterior

insula, a key network node, and the rest of the network was

strengthened (Cera et al., 2014).

1.3. Psychometric assessment

of neuroenhancement

Research groups typically rely on two types of psychometric

tests to assess altered neuropsychiatric states and provide

R.M. Battleday, A.-K. Brem1866

cognitive information to complement the type of biochemical

changes outlined above: 1) simple tasks, which involve basic

cognitive exercises targeting discrete sub-components of

cognitive functions; and, 2) more complex tasks, which

incorporate multiple difﬁculty levels and test more inte-

grated features of cognition. The former are typically devel-

oped for single-dose studies examining many subjects, and

have been well-validated for the detection of speciﬁc

cognitive deﬁcits in clinical populations (tests presented in

glossary form in Tab l e 2 ). In particular, sub-tasks of the

CANTAB test battery –a test series developed at the

University of Cambridge in 1986 from popular tests of non-

human primate cognition (Owen et al., 1990)–dominate this

literature. Conversely, the latter tend to be designed by

individual groups in order to assess more global functions.

Although more sensitive at detecting the cognitive changes of

speciﬁc interventions, they are more tasking to design and

administer, and, as they are less standardised, impose

difﬁculties on the comparison of results between studies.

2. Procedure

In order to evaluate the cognitive effect of modaﬁnil on

healthy adults, we conducted a systematic review of

relevant literature by searching MEDLINE with the terms

“modaﬁnil”and “cognitive”from January 1990 until

December 2014, and reviewed all resultant eligible studies.

We included studies for analysis if they were written in

English, prospective, conducted on healthy humans that

were not sleep-deprived, compared performance on mod-

aﬁnil to placebo, included randomisation protocols, and

contained at least one cognitive test (see Figure 1).

3. Results

Our search of the literature and subsequent selection

process resulted in 24 eligible studies, including both

parallel and cross-over designs. Within these studies, sev-

eral cognitive domains were well-represented, namely,

attention, executive function, learning and memory, and

creativity. The results of studies that employed simple

psychometric assessments to analyse these functions are

presented in Table 1, and reviewed by cognitive domain

below; a brief description of the tasks themselves may be

found in Table 2. The results of studies using more compli-

cated testing paradigms spanning multiple domains are also

presented in Table 1, and described at the end of this

section.

3.1. Attention

Attention is the cognitive function that allocates cognitive

resources to space, time, sense, and task (Posner, 2012): it

drives enhancement and suppression of relevant and

irrelevant sensory information, respectively, with the goal

of processing relevant information more accurately. The

most basic attentional sub-component is arousal, which is

associated to the intensity of attention (Berlyne, 1960),

and given modaﬁnil is licensed for its arousal-promoting

properties, it is unsurprising that many studies have

investigated its ability to promote or sustain various

attentional functions. Simple psychometric assessments

isolate and test alertness –reaction toward isolated stimuli

either without (tonic alertness) or with (phasic alertness) a

preceding warning stimulus; selective attention –the

ability to detect speciﬁc stimuli within an environment

containing distractors; sustained attention –the mainte-

nance of a consistent behavioural response during contin-

uous or repetitive activity; and, divided attention –the

ability to allocate cognitive resources to two or more

stimulus features or separate tasks (see Table 2;Sohlberg

and Mateer, 1987).

Although two studies demonstrated increased alertness

following modaﬁnil intake (Baranski et al., 2004;Randall

et al., 2005a,2005b), in the majority of studies no effect on

this sub-function was found (Baranski et al., 2004;Gilleen

et al., 2014;Liepert et al., 2004;Minzenberg et al., 2011;

Randall et al., 2003). Modaﬁnil intake had no effect on most

simple measures of selective attention (Marchant et al.,

2009;Müller et al., 2004;Randall et al., 2003,2004,2005a,

2005b), with the exception of one small study that showed

decreased reaction time with similar accuracy on the digit-

symbol substitution task (Makris et al., 2007). In terms of

sustained attention, again the majority of studies failed to

detect any improvement (Liepert et al., 2004;Müller et al.,

2004;Randall et al., 2003,2004;Theunissen et al., 2009;

Turner et al., 2003;Winder-Rhodes et al., 2010), with only

two studies reporting an improvement in performance with

modaﬁnil: one using the detection of repeated numbers task

(Baranski et al., 2004), and one the rapid visual information

processing task (Randall et al., 2005a,2005b). Finally, no

beneﬁts were found for divided attention following mod-

aﬁnil intake (Theunissen et al., 2009). In summary, studies

relying on simple tests of attention did not ﬁnd consistent

beneﬁts to modaﬁnil intake.

3.2. Executive function

Executive functions mediate the selection and manipulation

of incoming information, use of that information to con-

struct and initiate action plans, and enlistment of other

cognitive functions and brain regions into complex task-

oriented networks (Diamond, 2013). Enhancement of execu-

tive functions is the primary aim of many people seeking

and developing neuroenhancement, and modaﬁnil has anec-

dotally been thought to exert the largest effect on them.

Three core executive functions have been proposed,

namely, the inhibition of irrelevant information (inhibitory

control), the ability to alternate the focus of attention in

order to meet shifting task demands (cognitive ﬂexibility),

and the ability to hold and manipulate external and internal

information (working memory). Higher order executive

functions such as adaptive reasoning, problem solving,

planning, and decision making are hypothesised to evolve

from the interactions of these systems, as is ﬂuid intelli-

gence (Au et al., 2014).

3.2.1. Inhibitory control

Intermsofsimpletasks,Rycroft and colleagues (2007)

found that modaﬁnil intake improved inhibitory control on

an anti-saccade task, and one large between-subjects trial

demonstrated a beneﬁcial effect on the stop signal task

1867Modaﬁnil for cognitive neuroenhancement

Table 1 Results of literature review on cognitive effects of modaﬁnil in healthy non-sleep-deprived subjects.

Authors Number of

Participants

Study

Design

Dose Side

effects

Mood

changes

Cognitive domains assessed Effects observed

Baranski

et al.,

2004

18M PC;

DB; R;

4 mg/

–– Attention (DRN); executive function: logical reasoning

(LR) and mental addition (MA); motor: (SRT);

visuomotor/arousal; self-monitoring.

Improved accuracy on DRN; faster reaction time on

SRT. No effect on other domains.

Esposito

et al.,

2013

26M PC;

DB; R;

100 mg None –Executive function: ﬂuid intelligence (RAPM). No effect of group. Individuals taking modaﬁnil

demonstrated signiﬁcant improvement on medium

difﬁculty trials, whereas those on placebo did not.

Finke et al.,

2010

18 (9M) PC;

DB; R;

400 mg –Yes Attention (complex-TVA task). Improvement in visual attention of low baseline

performers: more objects processed, and increased

visual short-term memory storage capacity.

Geng et al.,

2013

26 (10M) PC;

DB; R;

200 mg –– Spatial attention and cognitive control. Increased successful selective spatial attention in low

probability conditions; increased attention/vigilance in

combination with enhanced cognitive control

mechanisms.

Gilleen

et al.,

2014

33 (13M) PC;

DB; R;

BS.

200 mg

(12

days)

Yes No Memory: language/implicit learning (complex multi-

day task, involving 10 days of cognitive training) and

short-term verbal memory (LM); transfer to measures

of general cognitive performance; motor: reaction

time (CCI).

Faster improvements in early training period of

language learning task; superior performance

maintained over ten day training period and at two

week follow up. Performance of high IQ group

improved to a greater extent than low IQ. No effect on

other measures.

Liepert and

Weiller,

2004

10 (10M) PC;

DB; R;

200 mg –– Attention (DC); motor: reaction time, dexterity (NPH)

and excitability (TMS-based).

No effect found.

Makris

et al.,

2007

11(5M) PC;

DB; R;

1.75/

3.5/7

mg/kg

–Yes Attention (DSS); memory: short-term verbal memory

(SNR) and learning and rule acquisition (RA).

Improved performance on DSS and RA. Decreased

reaction time on SNR.

Marchant

et al.,

2009

24 (7M) PC;

DB; R;

200 mg –Yes Attention (DSS); executive function: cognitive

ﬂexibility and working memory (complex task);

memory: prospective memory (PM) and short-term

verbal memory (FR).

Increased accuracy on complex attentional set shifting

task. No effect on DSS, PM, or FR.

Minzenberg

et al.,

2008

21 (12M) PC;

DB; R;

200 mg None Yes Executive function: inhibitory control (POP). No effect on POP when whole group analysed; sub-

group with sub-ceiling performance exhibited

improved accuracy.

Minzenberg

et al.,

2011

18 (10M) PC;

DB; R;

200 mg None No Visuomotor/arousal. Trend towards faster reaction time on arousal task.

Minzenberg

et al.,

2014

22 (12M) PC;

DB; R;

200 mg –– Executive function: inhibitory control (POP). No effect.

Mohamed,

2014

64 (31M)

(same

200 mg –Yes Marginally signiﬁcant improvement on GEF. No main

effect on ReA (but participants low in creativity

R.M. Battleday, A.-K. Brem1868

population

as below)

PC;

DB; R;

Short-term verbal (fDS) and visual (PAL) memory;

creativity: convergent (GEF, ReA) and divergent (AT,

LD, PM).

personality trait scored signiﬁcantly higher than those

high in creativity personality trait in modaﬁnil group

only). Reduced performance on ﬂexibility scores on the

AT. No effect on other tasks.

Mohamed

and

Lewis,

2014

64 (31M) PC;

DB; R;

200 mg None None Executive function: inhibitory control (HSC);

convergent thinking (HSC).

No effect on accuracy of HSC (slower reaction times in

inhibition section).

Müller

et al.,

2004

16 (10M) PC;

DB; R;

200 mg None No Attention (TMT-A, DC); numeric manipulation/working

memory (NWM); short-term visual memory (DMTS).

Fewer errors on NWM when difﬁcult manipulation

required only; “poor”baseline manipulators beneﬁtted

more than “good”. Decrease in error rates after long

delays only in DMTS. No effect on DC or TMT-A.

Müller

et al.,

2013

64 (31M) PC;

BD; R;

200 mg Yes Yes Executive function: planning (SOC) and working

memory (SWM, bDS); short-term memory (fDS, PAL);

creative thinking: convergent (LD, GEF) and divergent

(AT).

Improved performance on SOC, SWM, and PRM (delayed

only). No effect on other tasks.

Pringle

et al.,

2013

34 (17M) PC;

DB; R;

100 mg –Yes Executive function: working memory and cognitive

ﬂexibility (complex task), working memory (bDS);

short-term verbal memory (fDS).

Enhanced learning rate in complex learning task (rule

acquisition and set shifting): reﬂects executive

function (working memory and cognitive ﬂexibility). No

effect on DS.

Randall

et al.,

2003

30 (19M) PC;

DB; R;

100/

200 mg

–No Attention (TMT-A); executive function: inhibitory

control (Stroop), cognitive ﬂexibility (TMT-B), and

planning (SOC); short-term verbal (LM) and visual

memory (DMTS); clock drawing (CD); creativity

(COWA).

No effect found on any task.

Randall

et al.,

2004

45 (20M) PC;

DB; R;

100/

200 mg

–No Attention (TMT-A, RVIP); executive function: inhibitory

control (Stroop), cognitive ﬂexibility (TMT-B, IEDSS),

and planning (SOC); short-term verbal (LoM) and visual

(DMTS) memory; clock drawing (CD); creativity

(COWA).

200 mg group scored better on CD. 200 mg were faster

on congruent Stroop task (i.e., to name colour); No

effect on TMT-A, RVIP, SOC, TMT B, DMTS.), LoM, or

COWA. 200 mg scored worse on IEDSS.

Randall

et al.,

2005a,

2005b

60 (29M) PC;

BD; R;

100/

200 mg

–No Attention (TMT-A, DSS, DC, PASAT, RVIP); executive

function: inhibitory control (Stroop), cognitive

ﬂexibility (TMT-B, IEDSS), working memory (DST, SWM),

and planning (SOC); short-term verbal (fDS, LM) and

visual (PRM) memory; clock drawing (CD); creativity

(COWA); motor (RT).

Improved performance on PRM (200 mg were slower

during accurate trials). 200 mg more accurate and

sensitive on RVIP. 100 mg showed improved digit span.

200 mg group faster on congruent Stroop trials. No

effect on other trials, although drug group were faster

on easy trials, and slower on harder trials in the SOC.

Rasetti

et al.,

2010

38 (18M) PC;

DB; R;

100 mg

(7 days)

None No Attention (complex VAC task); executive function:

working memory (2-Back); visuomotor (VPC); emotion

(FMT).

No effect.

Rycroft

et al.,

2007

44 (44M) PC;

DB; R;

200 mg None No Executive function: inhibitory control (antisaccade

task).

Faster correct movements on an antisaccade task, did

not decrease (incorrect) prosaccades.

Theunissen

et al.,

2009

16 (5M) PC;

DB; R;

200 mg –– Attention (CT, MC, DA); executive function: inhibitory

control (SST).

Faster reaction time on MC. No effect on other tests.

1869Modaﬁnil for cognitive neuroenhancement

Table 1 (continued )

Authors Number of

Participants

Study

Design

Dose Side

effects

Mood

changes

Cognitive domains assessed Effects observed

Turner

et al.,

2003

60 (60M) PC;

DB; R;

100/

200 mg

–Yes Attention (RVIP); executive function: inhibitory control

(SS), cognitive ﬂexibility (IEDSS), working memory

(bDS, SWM); short-term verbal (fDS) and visual (PAL,

DMTS, SpS) memory; creative problem solving (CGT).

Improved performance on SOC, SST, and DS, PRM.

Longer latency/deliberation time in DMTS and CGT,

with similar accuracy. No effect on other tests.

Winder-

Rhodes

et al.,

2010

12 (12M) PC;

DB; R;

300 mg –– Attention (RVIP); executive function: inhibitory control

(SS), planning (SOC) and working memory (DO); short-

term visual memory (PRM); noradrenergic activity

(salivary alpha-amylase).

Fewer moves required on hardest difﬁculty of SOC. No

difference on other measures.

Studies are single-dose unless otherwise indicated. Abbreviations: M=male; PC =placebo-controlled; DB =double-blind; R=randomised; WS =within-subjects (i.e., crossover);

BW=between-subjects; TVA =theory of visual attention; IQ =intelligence quotient; TMS =transcranial magnetic stimulation; VAC =variable attentional control. For all other task

abbreviations see Table 2.

Table 2 Glossary of simple psychometric tests used in the assessment of modaﬁnil in healthy non-sleep-deprived humans.

Domain and Task Description

Attention

Selective attention

Trail-making task A (TMT-A) Participants sequentially connect 25 encircled numbers distributed on a sheet of paper by drawing straight lines between

them.

Digital-symbol substitution task (DSS) Participants use a table showing pairs of digits and hieroglyphic-like symbols to ‘translate’a series of symbol strings.

Symbol copying task (SC) Participants are presented with a sheet with 200 randomised symbols from the DSS (see above), and must copy as many

symbols as possible in the space and time provided.

Digit cancellation task (DC) The time taken to score out a given digit from random digit sequences is recorded, with errors.

Sustained attention

Critical tracking task (CT) Participants must reverse the horizontal deviation of a cursor from the midpoint of a horizontal line segment with

compensatory joystick movements.

Mackworth clock task (MC) Participants must detect a skip in the clockwise illumination of 60 grey dots on a computer screen.

Rapid visual information processing task (RVIP) Participants must detect letters/numbers and then determine whether they are immediately followed by another,

related, letter or number.

Detection of repeated numbers task (DRN) Participants must detect repeated numbers in a sequence of three-digit numbers, and write down the appropriate

number.

R.M. Battleday, A.-K. Brem1870

Divided attention

Divided attention task (DA) Participants perform the CT (see above) with the difﬁculty level ﬁxed at 50% of their maximum, but must remove their

foot from a pedal if a target number (e.g., “2”) appears as one of 24 single digits (0 to 9) that change asynchronously

every 5 seconds in the 4 corners of the computer screen (6 digits per corner).

Executive function

Inhibitory control

Stroop task Participants must press a button signalling a colour named by a visually presented word. In the experimental condition,

the colour of the letters making up the name differs from the colour the word describes, and participants typically take

longer to react appropriately.

Stop-signal task (SST) Participants must respond rapidly to visually-presented “go”signals with a key stroke, and inhibit any response when a

“stop”signal is suddenly presented.

Preparing to overcome prepotency task (POP) Participants must overcome instinctive or trained responses to various aspects of stimuli, in order to make a choice that is

incongruent to these features.

Antisaccade task Participants must ﬁxate on a small red circle in the centre of a computer screen. When the circle disappears, a

peripherally located red circle appears after 200 milliseconds, simultaneous with a tone. Participants must look and

quickly and accurately to the mirror location of the circle, whilst their eye movements are monitored automatically.

Variable attentional control task Participants must indicate the direction of a subset of arrows within an image (small, medium, or big). In low-control

conditions, non-salient arrows face the same direction as salient. In high control conditions, non-salient arrows act as

distractors, and face the opposite direction.

Working memory –verbal

Digit span task (backward) (bDS) Participants are required to immediately repeat a list of digits in reverse order, presented visually or verbally.

Digit ordering task (DO) Participants are read a string of numbers by an examiner, and then must repeat them, but in ascending order.

2-Back task Participants must identify the digit that occurred 2 digits ago in a series of sequentially presented digits.

Paced auditory serial addition task (PASAT) Participants must sum the two most recent digits from a serially presented set of single digits.

Numeric working number task (NWM) Participants must recognise if a four digit test sequence is ordered the same as a previously presented four digit

sequence. In the “easy”manipulation condition the middle two numbers have to be switched (positions 1-2-3-4 to 1-3-2-

4) and in the “difﬁcult”manipulation condition all four digits are re-ordered (positions 1-2-3-4 to 3-1-4-2).

Mental addition (MA) Participants must add a random sequence of eight numbers (between 1 and 16), presented serially.

Working memory –non-verbal

Spatial working memory task (SWM) Participants must search an increasing number of boxes (3–8) to locate hidden tokens, which were each located in the

same box per trial. Searching any box more than once each trial results in a ‘within search error,’while returning to

search an already emptied box incurs a ‘between search error.’

Spatial span task (backward) (SpS) Participants must touch an irregularly arranged series of boxes in the reverse order that they are touched by the

examiner.

Cognitive ﬂexibility

Intra/extra dimensional set shift task (IEDSS) The participant sees two colour-ﬁlled shapes, and must learn which is correct by touching them. After six correct

responses, the stimuli and/or rules are changed. These shifts are initially intra-dimensional (e.g., colour ﬁlled shapes

remain the only relevant dimension), then later extra-dimensional (white lines become the only relevant dimension).

Trail-making test B (TMT-B) Participants must draw lines sequentially connecting 25 encircled numbers and letters alternating between numbers and

letters.

Higher executive function

Logical reasoning task (LR) Participants must identify whether a statement displayed below two letters, A and B, truthfully describes their

relationship.

One-Touch Stockings of Cambridge/Tower of

Hanoi/Tower of London (SOC)

In the Stockings of Cambridge task, participants must rearrange coloured balls in vertical columns (“socks”) to match a

desired ﬁnal arrangement in a speciﬁed minimum number of moves. In the Tower of London version, participants must

instead move coloured balls between three “pegs”(“towers”).

1871Modaﬁnil for cognitive neuroenhancement

Table 2 (continued )

Domain and Task Description

Raven's advanced progressive matrices (RAPM) Participants must choose the correct visuospatial pattern from a set of ﬁxed alternatives, in order to complete a set of six

patterns that are related according to various logical principles.

Cambridge Gambling Task (CGT) Participants are presented with a row of ten red and blue boxes, and must guess in which colour a randomly-hidden yellow

token is hidden by pressing the red or blue button. Participants are offered ascending or descending bets based on their

colour choice, and must attempt to increase their “score”by betting on their choice being correct. The ratio of red and

blue boxes is varied between trials to examine a subject's decision-making behaviour.

Clock drawing task (CD) Participants must indicate the positions of the minute and hour hand according to a set of test-times on pre-drawn clock

faces.

Memory

Visual short-term memory

Spatial span task (forward) (SpS) Participants must copy the sequence with which an irregularly arranged series of boxes are highlighted.

Pattern recognition memory task (PRM) Participants are presented with a series of visual patterns, and must select the pattern that has been previously

presented.

Paired associates learning task (PAL) Participants are shown a set of boxes, which are opened at random to reveal a unique pattern. Participants are then

shown a cue pattern, and must select the box that contains it.

Delayed matching to sample task (DMTS) Participants are shown a complex visual pattern (the sample) and then, after a brief delay, four similar patterns.

Participant musts touch the pattern that matches the sample. Various adaptations of this test are in use.

Prospective memory task (PM) Participants must indicate whether letter strings presented on a computer screen are real English words or not. In

addition, participants must withhold their response and press the spacebar key if they saw a “PM”target (a letter string

containing only a single “P”or “Q”)

Repeated acquisition of response sequences (RA) Participants must learn a novel 10-response sequence, only using trial and error with four keys on a keypad. If the correct

key is pressed, a counter in the corner increases by one. Incorrect keystrokes cause the screen to turn blank for one

second, but do not alter the step counter.

Verbal short-term memory

Letter memory task (LM) Participants are told to mentally update a set of four most recent letters from a continuously presented stream of letters

and recall the last four when the stream is stopped.

Digit span task (forward) (fDS) Participants must immediately repeat a list of digits, presented visually or verbally. If they fail, a second list of the same

length is presented.

Sternberg number recognition task (SNR) Participants view a series of letters. Following a delay, participants are shown a probe letter and must indicate if it was

present in the series of letters. Various other versions of this task exist.

Immediate verbal free recall task (FR) Participants must write as many items as they remember from 20 serially-presented words.

Logical memory task (LoM) Participants are asked to recall a short story immediately after they hear it, and then 20 minutes later.

Creative thinking

Convergent thinking

Group embedded ﬁgures task (GEFT) Participants must identify a simple shape within a more complex ﬁgure.

Remote associate task (RA) Participants must give a word that has an associative linkage with three other given words.

Divergent thinking

Line drawing task (LD) Participants must list all the things they can think of when shown a series of line drawings.

Pattern meaning task (PaM) Participants must list all the things they can think of when shown a series of patterns.

Abbreviated Torrance task for adults –ﬁgure

subtask (AT)

R.M. Battleday, A.-K. Brem1872

(Turner et al., 2003); although notably two smaller cross-

over studies using similar doses did not (Theunissen et al.,

2009;Winder-Rhodes et al., 2010). By contrast, no effect

wasobservedonStrooptask(Randall et al., 2004,2005a,

2005b). In two studies using two preparing-to-overcome-

pre-potency paradigms, Minzenberg and colleagues failed

to detect an effect of modaﬁnil on task performance;

however, they both reported differences in brain activity

accompanying modaﬁnil intake. In the ﬁrst study, partici-

pants exhibited increased pre-frontal cortex (PFC) activity

(task-dependent), a decrease in locus coeruleus activity

(task-independent), and an increase in functional connec-

tivity between the locus coeruleus and the PFC

(Minzenberg et al., 2008). In the second, increases in

theta, alpha, and beta power in frontal and parietal

electroencephalography (EEG) electrode subgroups during

high-control subtasks were seen (Minzenberg et al., 2014).

Finally, Rasetti and colleagues conducted a seven-day

daily-dose trial in which functional magnetic resonance

imaging was performed during a variable attentional con-

trol task. Although no behavioural differences were

observed between modaﬁnil and placebo groups, image

analysis revealed decreased ACC activity following mod-

aﬁnil intake, taken by the authors to signify an increase in

computational efﬁciency in this area, which is richly

innervated by catecholaminergic neurons (Rasetti et al.,

2010).

3.2.2. Working memory

No effect was associated with modaﬁnil intake on many simple

tests of verbal working memory (Baranski et al., 2004;Gilleen

et al., 2014;Randall et al., 2005a,2005b;Winder-Rhodes,

2010). Studies reported mixed results using the backwards digit-

span task: three failed to show an effect (Müller et al., 2013 (a

large between-subjects study; 200 mg dose); Prin gle et al.,

2013 (a medium-sized between-subjects study; 100 mg dose);

Winder-Rhodes et al., 2010 (a small crossover study; 300 mg

dose)), whereas two trials –with equivalent participant num-

bers and doses –reported an increased span after modaﬁnil

intake (Randall et al., 2005a,2005b;Turner et al. 2003). Müller

and colleagues (2004) found that despite no overall improve-

ment in performance, on subtasks of the numeric working

memory task that required more manipulation, poor baseline

participants performed more accurately following modaﬁnil

ingestion. Finally, although Rasetti and colleagues found no

difference in task performance on a 2-Back task, decreased

activation was reported in right PFC during modaﬁnil sessions.

For non-verbal working memory, one large trial demonstrated

fewer between-search errors in the modaﬁnil group using the

spatial working memory task (Müller et al., 2013), whereas two

other large studies using similar doses did not (Randall et al.,

2005a,2005b;Turner et al. 2003).

3.2.3. Cognitive ﬂexibility

Most studies assessing cognitive ﬂexibility with simple tasks

reported no beneﬁt to modaﬁnil intake (Randall et al.,

2003,2005a,2005b;Turner et al. 2003), with one study

even reporting a decrease in performance on the intra/

extra dimensional set shift task (Randall et al., 2004).

Participants must complete a series of ﬁgures by adding lines and interesting shapes to them. They are instructed to try to

create unique objects and scenes, and attempt to create a picture or narrative that no other participant would think of.

Participants then have to name their drawing.

Alternative uses task (AU) Participants must state as many alternative uses as possible for a named object.

Hayling sentence completion test (HSC) Participants must listen to a sentence, then complete it by supplying the most appropriate last missing word (automatic

completion section) or by an unrelated word (inhibition section) as quickly as possible.

Motor

Nine-Hole-Peg task (NHP) Participants must place nine pegs into nine holes, and then remove them as fast as possible.

Four-choice serial reaction time (SR) Participants must move a visual pointer with a mouse to select one of four displayed letters, based on the identity of

serially presented probe letters.

CogState card identiﬁcation (CCI) Participants must indicate as quickly as possible whether a card is red or not as soon as it is revealed.

Emotion

Face matching task (FM) –emotional processing Participants must indicate which of two simultaneously presented matches the emotion displayed on a third face.

Only one study within this review uses a prospective memory task, and so its details are given here under this abbreviation. However, the reader should note that there are many tasks

that assess prospective memory, and the description given here refers only to one speciﬁc example of these tasks, and does not receive this abbreviation as standard elsewhere.

1873Modaﬁnil for cognitive neuroenhancement

3.2.4. Planning, decision-making, and ﬂuid intelligence

Many studies also examined higher executive functionality,

such as planning, decision making, and ﬂuid intelligence,

necessarily using more complicated tasks than those used

for lower functions. In terms of planning and decision

making, the Tower of London/One-Touch Stockings of Cam-

bridge tasks were well represented, with two large studies

reporting improved performance over all difﬁculties (Müller

et al., 2013;Turner et al., 2003), and one small study

reported improved performance on harder trials only

(Winder-Rhodes et al., 2010). Interestingly, although Ran-

dall and colleagues observed an increase in speed on easier

trials in keeping with the results above, they also found that

the modaﬁnil group exhibited decreased speed on harder

trials (Randall et al., 2005a,2005b). Finally, one small study

reported no differences between modaﬁnil and control

group performance (Randall et al., 2003).

Fluid intelligence is the ability to cope with novelty, to

think rapidly and ﬂexibly, and to see relations amongst

items independent of acquired knowledge, and is predictive

of life outcomes such as income, performance at work, and

health (Au et al., 2014;Sternberg et al., 2013). Using a

logical reasoning task that probed ﬂuid intelligence,

Baranski and colleagues (2004) found that modaﬁnil

increased accuracy. Similarly, Esposito and colleagues

reported that modaﬁnil intake improved one measure of

performance on Raven's Advanced Progressive Matrices, the

best-known assessment of ﬂuid intelligence. Although mod-

aﬁnil intake did not appear to affect overall performance

between individuals' pre-drug and post-drug performance,

individuals in the modaﬁnil group exhibited greater

improvement on medium difﬁculty trials than the control

group (Esposito et al., 2013).

In summary, modaﬁnil appears to exert a beneﬁcial effect

on executive functions, with some beneﬁts seen in inhibi-

tory control and working memory paradigms, and more

marked effects in higher executive functions such as plan-

ning, decision making, and ﬂuid intelligence.

3.3. Learning and memory

3.3.1. Non-verbal short-term memory

Makris and colleagues (2007) found that modaﬁnil increased

learning efﬁciency in a simple repeated acquisition of

sequences task. Several studies used the delayed matching

to sample task to evaluate modaﬁnil's effects on visual

short-term memory, with mixed results: two medium-sized

between-subjects studies using 100 and 200 mg doses failed

to demonstrate an effect (Randall et al., 2003,2004), one

smaller crossover study using 200 mg doses demonstrated a

decrease in error rate after long delay conditions (Müller

et al., 2004), and one large between-subjects study using

100 and 200 mg doses showed an increase in latency with

similar accuracy (Turner et al., 2003). Interestingly, a large

between-subjects study also showed a slowing of response

times in the modaﬁnil group on a similar visual short-term

memory task: the pattern recognition memory task; this

time with an improvement in performance (Randall et al.,

2005a,2005b). On the same task, another large between-

subjects study using similar doses showed a decrease in

incorrect choices with no effect on latency (Turner et al.,

2003), and a third found improved performance on delayed

but not immediate trials (Müller et al., 2013); by contrast, a

fourth small crossover study failed to reveal any effect from

300 mg of modaﬁnil (Winder-Rhodes et al., 2010). No effect

was observed on several other tasks (Mohamed, 2014;Müller

et al., 2013;Turner et al., 2003).

3.3.2. Verbal short-term memory

The results from studies assessing verbal short-term memory

were broadly similar: Markis and colleagues again showed

that modaﬁnil intake improved performance, this time on a

Sternberg number recognition task, with a concomitant

decrease in reaction time at 4 and 5 h (Makris et al.,

2007). Although several studies failed to show an effect

on the forward component of the digit span (Mohamed,

Figure 1 Flowchart of systematic search and selection protocol.

R.M. Battleday, A.-K. Brem1874

2014;Müller et al., 2013;Pringle et al., 2013;Winder-

Rhodes et al., 2010), two large trials did report a positive

effect (Randall et al., 2005a,2005b;Turner et al. 2003). No

effect was seen on several other measures (Marchant et al.,

2009;Randall et al., 2003,2004,2005a,2005b).

In summary, some beneﬁts were seen with modaﬁnil on

simple assessments on learning and memory, including both

early and delayed performance. However, an equal number

of studies failed to observe any effect.

3.4. Creativity

In cognitive science, creativity is formally deﬁned as the

production of ideas and work that is both novel and

appropriate (Dietrich, 2004), and has traditionally been

thought to arise from cognitive and neural systems distinct

from the domains involved with classical “intelligence”

outlined above (although see Nusbaum and Silvia (2011)).

Further, there is consensus that two broad creative sub-

functions exist: convergent and divergent thinking. Con-

vergent thinking underlies problem-solving abilities: arriving

at a particular strategy and solution to link two disparate

concepts (Mohamed, 2014). Modaﬁnil intake did not affect

convergent thinking in most studies (Mohamed and Lewis,

2014;Mohamed, 2014;Müller et al., 2013); however, when

participants were separated into low- and high-creativity

personalities in Mohamed's study –based on a pre-

assessment personality questionnaire –participants with

low creativity personalities were seen to score signiﬁcantly

higher than those with high baseline creativity in the

modaﬁnil group only (Mohamed, 2014). In contrast, diver-

gent thinking relies on a person's ability to generate multi-

ple associations or solutions to a subject or problem

(Mohamed, 2014). Most studies did not report any effect

of modaﬁnil on simple divergent thinking paradigms

(Mohamed, 2014;Müller et al., 2013;Randall et al., 2003,

2004,2005a,2005b). In a few studies, however, impaired

performance was observed in the modaﬁnil group:

decreased ﬂuency and elaboration on the abbreviated

Torrance task (Mohamed, 2014); increased deliberation time

on the Cambridge gambling task with no change in accuracy

(Turner et al., 2003); and slower reaction times in the

inhibition section of the Hayling sentence completion test

(Mohamed and Lewis, 2014).

3.5. Complex tasks

Most of the tasks above are ‘simple’in that they selectively

assess one or two cognitive sub-functions. However, with

testing of higher executive functions, which as noted are

thought to rely on separately testable sub-functions, task

procedures become more complicated, as do their results.

Equally, their relevance is altered: tests assessing higher

functions immediately appear more ecologically valid. The

‘complex’tasks described below extend this framework, and

use one or more advanced psychometric tasks to assess more

global cognitive domains, typically also varying task difﬁ-

culty. They are therefore also able to gather more informa-

tion about different aspects of participants' performances:

learning rates and value associations, in addition to reaction

times and accuracies. However, these tests have mainly been

used to test speciﬁc hypotheses about cognitive functioning,

and consequently remain less well standardised. This means

they are less suited to monitoring permutations of already

well-described cognitive sub-functions, as their results are

harder to generalise, and less evidence exists as to their

modulation by different cognitive states.

Pringle and colleagues examined the effects of modaﬁnil

versus placebo in a compound learning task that also relied

on attention and executive function. In this task, a set of two

objects were brieﬂy shown on a screen, followed by one or

two dots in the position previously occupied by one of the

objects, and participants were instructed to indicate the

number of dots present as quickly as possible. In the ﬁrst set

of trials, dot location was predicted by particular object

features, for example, the object coloured red. Then,

representing an intra-dimensional switch, another colour

became predictive in the second set of stimuli; in the third

a different stimulus dimension –the shape of the object –

became predictive (an extra-dimensional switch); and in the

fourth, another shape became the salient indicator. Modaﬁnil

intake not only improved learning rates following the extra-

dimensional shift, but also increased participants' accuracy

across all blocks. The authors attribute this difference to

better orientation of sustained attention in the modaﬁnil

group, driven by enhanced cognitive ﬂexibility, decision

making, and rule acquisition (Pringle et al., 2 013).

In Marchant and colleagues' paradigm, stimuli were

concurrently presented in visual and auditory streams, and

participants had to identify non-targets and targets. In the

constant condition, participants were informed that the

target stimulus would be red objects in the ﬁrst set of trials,

and a low tone in the second. Thus, this section tested

selective and sustained attention, and inhibitory control. In

the alternating condition, participants were told that the

salient stimulus dimension would alternate between red

stimuli and the low tone; thus this section additionally

probes short-term memory and cognitive ﬂexibility. In the

constant condition, all participants were more accurate at

identifying non-targets rather than targets (this was unsur-

prising, as non-targets were presented at a higher fre-

quency), with no differences observed between modaﬁnil

and placebo groups. In the alternating condition, however,

subjects taking modaﬁnil responded to non-targets and

targets with similar accuracy (near-maximal), whereas

those taking placebo did not detect targets with the same

high accuracy as non-targets (Marchant et al., 2009); an

effect suggestive of enhanced attentional and executive

functions.

Geng and colleagues employed a decision-making task

based on spatial probability, in which subjects were

instructed to guess which of two boxes a stimulus would

appear in. For the ﬁrst 200 trials, the stimulus was

presented at one location 70% of the time; in the second

200 trials, the stimulus was presented in either location 50%

of the time. Modaﬁnil intake was found to improve the rate

at which subjects learnt the spatial probabilities underlying

their choices, again attributed to an enhancement of

executive functions with more accurate orientation of

attention as a corollary (Geng et al., 2013).

Finke and colleagues analysed participants' performance

on a whole report task, according to the “theory of visual

attention”model. In this task, participants viewed a column

1875Modaﬁnil for cognitive neuroenhancement

of ﬁve simultaneously presented letters for a brief period of

time, followed by either blank space (the “unmasked”

condition) or an identically positioned column of ﬁve crosses

(the “masked”condition). Stimuli were presented for a

variable amount of time, and, after a variable pause

(masked or unmasked), participants were instructed to

recall as many of the letters as possible. According to the

theory of attention model, visual objects are processed in

parallel, and compete for space in a visual short-term

memory store according to the attentional weighting they

receive. Modaﬁnil was found to increase the uptake of

information (in other words, processing speed) in low base-

line performers, as well as the storage capacity in this

group. The authors again posit that these beneﬁts were

probably due to modaﬁnil's upregulation of PFC-based

processes involved in executive function, manifesting in

improved attentional functions (Finke et al., 2010).

Gilleen and colleagues combined cognitive training on a

language learning paradigm with twelve days of either

modaﬁnil or placebo intake. In their task, auditory neolo-

gisms were presented with a visual object within a rapidly

presented series. 50 word-picture combinations were target

pairings –these were presented twice as frequently –

whereas all other combinations were unpaired. After each

pairing was presented, participants had to identify whether

it was a target or not, with the only indicator being the

increased incidence of target pairings, and experience in

previous days. This task relies on multiple memory domains,

as well as attentional components, and those taking mod-

aﬁnil exhibited enhanced learning rates early in the training

period, and maintained superior performance overall, and

at follow up two weeks later. Notably, those with high

baseline intelligence scores –measured using the Wechsler

Abbreviated Scale of Intelligence –progressed more quickly

in the modaﬁnil group than those with low baseline intelli-

gence scores on all days of training (1–10), an effect not

seen in the placebo group (Gilleen et al., 2014).

When these results are considered together, it appears

that modaﬁnil exerts a complex effect on cognitive

domains, in general driving beneﬁts in attention and

memory through enhancement of higher executive func-

tions. Positive results are observed in all of these studies,

suggesting increased testing times and more complicated

paradigms might be necessary to consistently reveal the

cognitive beneﬁts of modaﬁnil intake.

3.6. Alteration of mood and side effects

70% of studies assessed the inﬂuence of modaﬁnil intake on

mood, and although a small number of studies reported a

clustering of positive effects centred on the ability of

modaﬁnil to promote alertness/energy and ameliorate

feelings of tiredness, the majority reported no changes.

Notably, very few studies reported potentially negative

effects, such as increased anxiety (Randall et al., 2003)

and decreased contentedness (Marchant et al., 2009). Nine

out of 24 (37.5%) of the studies in our review reported side

effects: of these, 78% reported no side effects, and the

remaining two reported that a small minority of participants

had experienced insomnia, headache, stomach ache or

nausea, and dry mouth (Gilleen et al., 2014;Müller et al.,

2013). Further, modaﬁnil did not appear to affect motor

excitability (Liepert et al., 2004). Encouragingly, the only

study to assess modaﬁnil's abuse potential corroborates

consensus that it is low (Makris et al., 2007).

4. Discussion

4.1. Summary

When simple psychometric assessments are considered,

modaﬁnil intake appears to enhance executive function,

variably beneﬁt attention and learning and memory, and

have little effect on creativity and motor excitability. When

more complex tasks are considered, modaﬁnil appears to

enhance attention, higher executive functions, and learning

and memory. Negative cognitive consequences of modaﬁnil

intake were reported in a small minority of tasks, and never

consistently on any one: decreased performance on a

cognitive ﬂexibility task (the intra/extra-dimensional set

shift task in Randall et al. (2004)), increased deliberation

time during harder trials on a planning task (the One-Touch

Stockings of Cambridge task in Randall et al. (2005a,

2005b)), increased deliberation time on one divergent

thinking task (the Cambridge Gambling Task in Turner

et al. (2003)), and decreased performance on another (the

abbreviated Torrance in Mohamed (2014)). It appears that

modaﬁnil exerts minimal effects on mood –if anything

improving it –and only rarely causes minor adverse effects.

4.2. Mechanistic speculations

These ﬁndings are in keeping with the effects reported in

clinical and sleep-deprived populations (Minzenberg and

Carter, 2008;Mohamed and Lewis, 2014), and are supported

by the molecular, imaging, and electrophysiological litera-

ture, allowing speculation as to the cognitive mechanisms

by which modaﬁnil might engender neuroenhancement.

Modaﬁnil is known to amplify endogenous arousal systems,

seen in pupillography (Hou et al., 2005), hormone and

enzyme levels (Samuels and Hou, 2006;Winder-Rhodes

et al., 2010), imaging (Minzenberg et al., 2008), and

electrophysiology (Della Marca et al., 2004). As arousal

subserves all other attentional capacities, which in turn

underlie many aspects of higher cognition, it is conceivable

that this ‘bottom-up’effect is responsible for the beneﬁts

observed on simple measures of attention, executive func-

tion, learning and memory following modaﬁnil intake.

Certainly, an increase in arousal could explain observations

that modaﬁnil ampliﬁes task-induced deactivation of the

“default mode network”–which is active in the absence of

salient stimuli or attention-demanding tasks (Minzenberg

et al., 2011), or the brainstem-based potentiation of

somatosensory-driven high frequency oscillations (Della

Marca et al., 2004). However, on most direct measures of

arousal itself, no beneﬁt to modaﬁnil intake was seen.

Instead, a more compelling theory is that modaﬁnil stimu-

lates improved performance in the range of tasks reported

herein mainly as a downstream effect of enhancement of

‘top-down’cognitive control processes. Behaviour support

for this second theory comes from the consistently improved

performance in executive function paradigms, and positive

R.M. Battleday, A.-K. Brem1876

results from complex trials primarily involving these func-

tions. Further, the task-related changes in ACC and PFC

activity during executive control tasks (Minzenberg et al.,

2008;Rasetti et al., 2010), as well as in EEG alpha, beta,

and theta activity (Minzenberg et al., 2014), are also

consistent with ampliﬁcation of activity in executive-

control-related brain regions (which are richly innervated

by catecholaminergic neurons (Rasetti et al., 2010)).

Such a theory is undoubtedly a simpliﬁcation of the

intricate effect of modaﬁnil on the networks underlying

cognition. The more marked improvements on tasks asses-

sing multiple cognitive domains and sub-domains –as well as

the permutation of many major neurotransmitter systems –

indicate that there is much more to be discovered about this

interaction. As our theories of intelligence increasingly

follow a neural network philosophy (Jung and Haier,

2007), perhaps the neuronal causality of modaﬁnil's cogni-

tive effects will be more faithfully explicated. Indeed, the

value of this approach can be seen in the imaging studies

above, where modaﬁnil intake increases blood ﬂow to

diverse network and speciﬁc regions, including the hippo-

campus, (Joo et al., 2008), and activates multi-areal brain

networks subserving attention and executive functions

(Esposito et al., 2013) and multiple cortical areas during

associative learning (Ghahremani et al., 2011).

Finally, discrepancies in the relationship between mod-

aﬁnil intake and speed of cognitive processing reported

above merit further discussion. In attention- and executive

function-based paradigms, modaﬁnil on average improved

immediate reaction times, with or without enhanced accu-

racy. However, in short-term memory studies, the beneﬁts

of modaﬁnil were most marked in delayed recognition

conditions, and in some tests of planning and creativity,

increased deliberation time was seen in the modaﬁnil

group, without improved performance. These ﬁndings on

one hand imply that modaﬁnil intake assists with focussing

cognitive resources on attention-based tasks, endowing

beneﬁts on rapid and delayed singular responses, but also

hint that these improvements have the unwanted corollary

of impairing functions that beneﬁt from more protracted

contemplation. It is essential that future work analyses

these effects more rigorously.

4.3. Methodological points

The discrepancy between the mainly null results from

simple tests, with the exception of those assessing execu-

tive functions, and the mainly positive results from more

complex testing paradigms highlighted by this review war-

rants further discussion and investigation. In terms of

complex tasks, a systematic bias towards positive results

could have been introduced through study design or study

execution (a universal bias from task design is less likely

because of the varied nature of these tasks). One source of

study-design-based error could be the equal weighting we

have accorded to results from crossover and between-

subject trials. In the former, a participant's performance

on a test under one condition (for example, modaﬁnil

intake) is compared to their own performance under

another condition (for example, placebo), and in the latter

one group's performance under one condition on a test is

compared to a control group's performance on the same

test. It has been argued that repeating psychometric tests in

crossover tests introduces practice effects that vary unpre-

dictably between individuals and cognitive tasks, and could

bias results (Hartley et al., 2003;Lowe and Rabbitt, 1998;

Randall et al., 2004;Rose and Lin, 1984). Fortunately,

however, the preponderance for each study design is

roughly equal within simple and complex task groups, and

repeated dose studies use complex tasks with adaptive

assessment platforms that should obviate these practice

effects. Equally, the prolonged testing experience asso-

ciated with complex tasks may have allowed more oppor-

tunities for experimenters to inﬂuence participants. Against

this argument is the fact that in the two studies that did

assess participant blinding, participants were able to guess

they had taken modaﬁnil 55% of the time in a complex

crossover trial (Gilleen et al., 2014), but 75% in a simple

between-subjects study (Turner et al., 2003).

Conversely, the simple psychometric tasks used by the

majority of studies could have lacked sufﬁcient sensitivity

to detect cognitive effects in the healthy and mostly

student-based populations tested. With this in mind, it is

a notable non sequitur that tests that reliably report

cognitive dysfunction are equally qualiﬁed to detect

improved cognitive performance in healthy adults. A key

example of the inadequacy of some testing paradigms is the

use of the “clock test”in some of these studies, which

involves drawing hands onto a clock at speciﬁc times (for

example, in Randall et al. (2005a,2005b)). Whilst in ill

populations this test offers a valuable screening tool of poor

cognitive function (Shulman, 2000), it is clearly a poor

differentiator of normal or high-performing healthy indivi-

duals. Indeed, ceiling performances were consistently

observed within simple tasks, for example on the pattern

recognition memory task (Müller et al., 2013;Randall et al.,

2005a,2005b;Turner et al., 2003;Winder-Rhodes et al.,

2010), the delayed matching to sample task (Randall et al.,

2003,2004;Turner et al., 2003), the rapid visual informa-

tion processing task (Randall et al., 2005a,2005b), the

spatial working memory task (Turner et al., 2003;Winder-

Rhodes et al., 2010), the preparing-to-overcome-pre-

potency tasks (Minzenberg et al., 2008,2014), and the

Sternberg number recognition task (Makris et al., 2007).

When these ceiling effects were lessened by only analysing

data from low baseline performers, many studies actually

did detect signiﬁcant differences between modaﬁnil and

placebo groups (Minzenberg et al., 2014;Mohamed, 2014;

Müller et al., 2004;Randall et al., 2005b). Several groups

have commented this issue, noting, for example, that it may

explain why robust effects on these same tasks are seen

with sleep deprivation (Müller et al., 2004), when all

participants effectively become low baseline performers.

They also suggest that these tasks are in their current state

inappropriate for detailed assessment of healthy individuals

(Müller et al., 2004), and must be revised or abandoned in

favour of more complex testing paradigms (Finke et al.,

2010;Müller et al., 2013;Pringle et al., 2013). Recognition

of the limitations of simple psychometric tests is also seen

in the temporal succession of simple with complex ones over

the last decade. Thus, it appears that within research on

modaﬁnil, any consensus about cognitive beneﬁts has to this

point been limited by the use of simplistic testing

1877Modaﬁnil for cognitive neuroenhancement

paradigms. These ceiling effects must be addressed in

future work; certainly before discourse on the ability of

low and high baseline participants to beneﬁt from modaﬁnil

can offer real value.

4.4. Recommendations for future studies of

neuroenhancement techniques and agents

If the literature surrounding modaﬁnil—one of the most

promising and highly-investigated neuroenhancers to date—

presents this many barriers to comparison and interpreta-

tion, it stands to reason that cognitive assessment of

neuroenhancement in general may beneﬁt from the devel-

opment of novel or improved methodological approaches.

As the ﬁrst stage in this process, and in order to guide future

neuroenhancement studies, we propose the following fra-

mework, centred on the principles of, on one hand,

sensitivity and reproducibility, and, on the other, ecological

validity (see Table 3).

The ‘simple’task designs described above are extremely

useful tools for dissecting the inﬂuence of a substance or

process on higher cognitive functions. Equally important,

their internal validity is high, at least within clinical

populations (Levaux et al., 2007;Sweeney et al., 2000).

Hence, if the ceiling effects encountered in these studies

could be ameliorated, they would still add much valuable

information to any assessment of supra-normal cognition.

One solution to this problem is to integrate them into more

advanced software platforms, which would still be standar-

dised, but could be set to increase task difﬁculty via more

complex task demands and shorter response windows. More

complex tasks could then be integrated into the basic

software package as additional modules, meaning more

nebulous domains and cognitive processes could be investi-

gated with reference to changes in basic systems, and a high

internal consistency in the literature could be established.

The additional advantages of such an approach are myriad:

integration of adaptive training and testing regimes, so that

learning in each cognitive-subdomain could also be mea-

sured; more comprehensive analysis of participant perfor-

mance, with the ability to compare every aspect of their

actions; and game-based incentive structures, obviating the

decline in performance that follows prolonged testing

(Kennedy and Scholey, 2004). Using the same system,

testing could be conducted on untrained tasks and their

cognitive sub-domains, to identify any transfer of cognitive

ability (see Gilleen et al. (2014), or be used for re-testing at

later dates, to identify lasting effects.

The output of neuroenhancement-related research is

aimed at a fundamentally different population from most

prior work on cognitive modulation –those seeking elective

self-improvement of their own cognitive abilities, rather

than those hoping to treat cognitive deﬁcits. Consequently,

methodologies of research in this area need to be consid-

ered anew, in order to probe supra-normal cognitive

enhancement in ecologically valid settings whilst retaining

rigorous testing conditions. Most tasks and projects in life

necessitate learning and operating within a system for

multiple days, and individual users are interested primarily

in how their own performance will change, rather than the

average of a group. Thus, testing regimes should be based

over multiple days, and allow analysis within and between

single participants' performances. Baseline testing is also

essential; as an absolute measure of individual perfor-

mance, to ensure that ceiling and ﬂoor performances are

not limiting the usefulness of results, and to allow specula-

tion on whether and why some groups beneﬁt more from

particular agents or techniques. Makris and colleagues'

(2007) ﬁnding of improved reaction times four and ﬁve

hours after modaﬁnil ingestion serves as a reminder that

under real-life conditions, performance is likely to be

affected by fatigue even within a single working day. In this

case, modaﬁnil's eugeroic properties are evidently beneﬁ-

cial; however, more generally studies should make more

effort to examine the length of performance beneﬁts

offered by an agent or technique for neuroenhancement.

Finally, in the set of studies we examined, reporting of

side effects was egregiously low and inconsistent. Given the

potentially far-reaching consequences of neuroenhance-

ment research, future studies must be required to report

side effects, using a rigorous and standardized system.

5. Conclusion

In this review, we have highlighted that modaﬁnil provides

some beneﬁt to cognition, in particular executive functions,

speculated on the mechanisms by which it may do so, and

offered critical analysis on the methodology that has been

employed to date in healthy, non-sleep-deprived indivi-

duals. As this is a retrospective analysis, we must emphasise

that these conclusions and explanations remain necessarily

weaker than if integrated into prospective study questions;

indeed, this is a secondary and explicit aim of the text.

A full discussion of the rationale for, possibility of, and

ethical issues surrounding neuroenhancement is beyond the

scope of this review (for attempts at such, see Maslen et al.

(2014) and Persson and Savulescu (2008)). However, it is

Table 3 Methodological recommendations for neuroen-

hancement studies.

Task design

In order to attain the sensitivity to detect supra-normal

improvements in cognition, studies should use

computer-based assessment paradigms that:

1. Are designed for use in healthy rather than clinical or

animal populations;

2. Focus on one or more cognitive domains and their sub-

domains;

3. Integrate adaptive training and testing components;

4. Include testing on other un-trained cognitive domains.

Trial design

In order to emulate real-world conditions surrounding

ideal use of neuroenhancement, studies should:

1. Test over multiple days;

2. Include follow-up testing;

3. Use a design that includes between-subjects and

within-subjects testing;

4. Include analysis of high and low baseline performers;

5. Be required to report side effects using a

standardized and rigorous system.

R.M. Battleday, A.-K. Brem1878

noteworthy that with more protracted and complex testing,

more beneﬁts are being associated with modaﬁnil use rather

than less, which suggests that modaﬁnil may well deserve

the title of the ﬁrst well-validated pharmaceutical ‘noo-

tropic’agent. This observation is also true of non-invasive

brain stimulation techniques, in which more integrative

cognitive assessments and physiological recordings are

yielding increasingly valuable insights into the mechanisms

by which they may engender cognitive enhancement (see,

for example, Battleday et al. (2014) and Santarnecchi et al.

(2015)). In this vein, we hope our recommendations for

future study will assist in advancing and consolidating the

cognitive investigation of neuroenhancement agents, and,

in doing so, contribute valuable information to wider

discourse on the achievability and role of neuroenhance-

ment within wider society.

Conﬂict of interests

The authors declare no conﬂict of interests.

Contributors

R.M. Battleday conducted the literature review and wrote the

article. A-K. Brem assisted with critical analysis and writing the

article.

Funding source

This work was conducted without any input from funding

sources.

Acknowledgements

None.

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1881Modaﬁnil for cognitive neuroenhancement

Clinical and Pharmacological Characteristics of the Drug Modafinil

Article

Nov 2023

В Республике Беларусь зарегистрирована субстанция лекарственного вещества модафинил. До настоящего времени это первая субстанция данного вещества, произведенного на территории государств постсоветского пространства. Представлены результаты анализа литературных источников, и дана клинико-фармакологическая характеристика лекарственного вещества модафинил. Отражены данные клинических исследований использования модафинила, его эффектов, показаний, противопоказаний, а также результаты исследований воздействия модафинила на когнитивные функции, психическую работоспособность и способность повышать концентрацию внимания. The substance of the medicinal substance modafinil is registered in the Republic of Belarus. To date, this is the first substance of this substance produced on the territory of the post-Soviet states. The results of the analysis of literary sources are presented and the clinical and pharmacological characteristics of the medicinal substance modafinil are given. The data of clinical studies of the use of modafinil, its effects, indications, contraindications, as well as the results of studies of the effects of modafinil on cognitive functions, mental performance and the ability to increase concentration are reflected.

Lights, camera, cognition: Unveiling the Neurocognitive Effects of Modafinil in Actors

Article

Full-text available

Jan 2023

In the dynamic intersection of cognitive enhancement and artistic expression, this article explores the cognitive neuroeffects of modafinil on the cognitive abilities of actors and investigates its potential impact on the inherent cognitive domains crucial to the entertainment industry. Employing a comprehensive experimental approach, professional actors of diverse backgrounds utilized modafinil to uncover its effects on sustained attention, working memory, creativity, emotional recognition, cognitive flexibility, and emotional intelligence. The findings reveal significant improvements in attention accuracy, working memory precision, heightened creative output, emotional recognition acuity, cognitive flexibility, and emotional intelligence within the modafinil group when compared to the placebo. These effects stem from the modulation of neural chemical pathways governing attention, memory, emotional processing, and cognitive flexibility by modafinil. The results affirm modafinil as a cognitive enhancer for actors, optimizing their executive intelligence while heightening ethical considerations and potential challenges. This exploration of modafinil's cognitive effects in the realm of acting contributes valuable insights to cognitive enhancement research and paves the way for the integration of pharmacological interventions in creative professions.

The ASAM/AAAP Clinical Practice Guideline on the Management of Stimulant Use Disorder

Article

Full-text available

May 2024

Comparison of effects of modafinil and caffeine on fatigue-vulnerable and fatigue-resistant aircrew after a limited period of sleep deprivation

Article

Full-text available

Jan 2024

Introduction: Literature suggests pilots experience fatigue differently. So-called fatigue-resistant or -vulnerable individuals might also respond differently to countermeasures or stimulants. This study, which is part of a larger randomized controlled clinical trial, aims to investigate the effect of caffeine and modafinil on fatigue-resistant and -vulnerable pilots. Methods: This study included 32 healthy employees of the Royal Netherlands Air Force, who completed three test days, separated by at least 7 days. After a regular work day, the subjects were randomly administered either 300 mg caffeine, 200 mg modafinil or placebo at midnight. Hereafter the subjects performed the psychomotor vigilance test (PVT), vigilance and tracking test (VigTrack) and Stanford sleepiness scale (SSS) six times until 8 a.m. the next day. Subjects were ranked on the average number of lapses on the PVT during the placebo night and divided into three groups: fatigue-vulnerable (FVUL), -intermediate (FINT) and -resistant (FRES), with 11, 10 and 11 subjects in each group, respectively. Area under the curve (AUC) of the PVT, VigTrack and SSS during the test nights were calculated, which were used in univariate factorial analysis of variance (ANOVA). Tukey’s HSD post hoc tests were used to differentiate between the groups. Results: A significant effect of treatment was found in the ANOVA of both PVT parameters, VigTrack mean reaction time and SSS. There was a statistically significant effect of fatigue group on all PVT parameters and VigTrack mean percentage omissions, where FINT and FRES scored better than FVUL. There was a significant interaction effect between treatment and fatigue group for PVT number of lapses. This is congruent for the AUC analyses in which for all parameters (except for the SSS) the performance of the FVUL group was consistently worse than that of the FINT and FRES groups. Discussion: This study demonstrates that the performance of individuals with different fatigue tolerances are differently affected by simulants after a limited period of sleep deprivation. The classification of fatigue tolerance through PVT lapses when sleep deprived seems to be able to predict this.

Pharmacological cognitive enhancement substances: Prevalence of study drug use and contributing stressors among university students

Thesis

Full-text available

May 2022

Emma Jespersen

This research aims to estimate the prevalence of pharmacological cognitive enhancement (PCE) substances among students in UK universities, along with confirming which stressors users believe have contributed towards their use of such drugs. Due to most research on “study drugs” having been undertaken in the US, the prevalence of substance use with cognitive aims is not known in the UK. A questionnaire was distributed online amongst Durham, Cambridge, Newcastle, and Edinburgh students, which asked about potential drug use and, if relevant, if and what stressors contributed towards their decision to use PCE- drugs. While the survey gained traction amongst Cambridge and Durham students, it failed to produce an adequate number of responses from the other universities. A total of 192 responses were recorded. The main findings showed that the rate of PCE-use in the sample was 11%, with the true population estimate likely existing in the interval 7.01-16.58%. Men were found to be more likely than women to use PCE-drugs (p-value: 0.033). Respondents indicated that, of the listed stressors, academic procrastination along with feelings of being “burnt out” contributed most towards their decision to use PCE-drugs. Further research on the subject of PCE-use is encouraged so that estimates of prevalence can continue to be improved and understanding behind the motive to use enhancement drugs is advanced.

The Atypical Dopamine Transporter Inhibitor CE-158 Enhances Dopamine Neurotransmission in the Prefrontal Cortex of Male Rats: A Behavioral, Electrophysiological, and Microdialysis Study

Article

Full-text available

Sep 2023
INT J NEUROPSYCHOPH

Background: Dopamine plays a key role in several physiological functions such as motor control, learning and memory, motivation and reward. The atypical dopamine transporter inhibitor CE-158 has been recently reported to promote behavioral flexibility and restore learning and memory in aged rats. Methods: Adult male rats were intraperitoneally administered for 1 or 10 days with CE-158 at the dose of 1 or 10 mg/kg, and tested for extracellular dopamine in the medial prefrontal cortex (mPFC) by means of intracerebral microdialysis and single unit cell recording in the same brain area. Moreover, the effects of acute and chronic CE-158 on exploratory behavior, locomotor activity, prepulse inhibition (PPI), working memory and behavioral flexibility were also investigated. Results: CE-158 dose-dependently potentiates dopamine neurotransmission in the mPFC as assessed by intracerebral microdialysis. Moreover, repeated exposure to CE-158 at 1 mg/kg is sufficient to increase the number of active pyramidal neurons and their firing frequency in the same brain area. In addition, CE-158 at the dose of 10 mg/kg stimulates exploratory behavior to the same extent after acute or chronic treatment. Noteworthy, the chronic treatment at both doses did not induce any behavioral alterations suggestive of abuse potential (e.g., motor behavioral sensitization) or pro-psychotic-like effects such as disruption of sensorimotor gating or impairments in working memory and behavioral flexibility as measured by PPI and Y maze. Conclusions: Altogether, these findings confirm CE-158 as a promising pro-cognitive agent and contribute to assessing its preclinical safety profile in a chronic administration regimen for further translational testing.

Effects of Caffeine on Main Symptoms in Children with ADHD: A Systematic Review and Meta-Analysis of Randomized Trials

Article

Full-text available

Sep 2023
BSRCCS

(1) Background: Attention-deficit/hyperactivity disorder (ADHD) is typically treated with stimulant medications, which may lead to several adverse effects. Recent animal studies have shown that caffeine can improve the symptoms of ADHD. This systematic review and meta-analysis sought to evaluate the effect of caffeine on ADHD symptoms in children. (2) Methods: PubMed, Embase, and Cochrane databases were searched for randomized controlled trials comparing caffeine with placebo in children, comparing overall symptoms of ADHD, inattention, hyperactivity, and impulsivity. (3) Results: We included seven RCTs in the systematic review for qualitative assessment, with 104 patients aged 5 to 15 years. Four of these studies (n = 76) were included in the meta-analysis. After qualitative analysis, four studies indicated no improvement in any of the ADHD symptoms compared with placebo. One study showed improvement in ADHD symptoms based on 1 of 5 scales applied. One study indicated significant improvement in general symptoms, inattention, and hyperactivity. One study indicated improvement in sustained attention but a worsening of impulsivity. In contrast, when using a quantitative analysis of the general symptoms of ADHD, the data showed no significant difference when comparing placebo with caffeine (standardized mean difference −0.12; 95% CI −0.44 to 0.20; p = 0.45; I2 = 0%). (4) Conclusion: overall, the totality of the evidence suggests no significant benefit of caffeine over placebo in the treatment of children with ADHD.

Student Cognitive Enhancement with Non-Prescribed Modafinil. Is it Cheating?

Preprint

Full-text available

Mar 2024

Modafinil, a prescription-only drug, it is mainly used to treat narcolepsy and sleep disorders, but it is also used, without a prescription, as a cognitive enhancer by ~10% of UK University students. Previous research has focused on the prevalence of, and motivations for, these behaviours. Here we focused specifically on determining whether students view this behaviour as cheating. We used a scenario-based approach to quantify, and qualitatively understand, student views on this topic. Most students did not view this behaviour as cheating, in part due to similarities with freely available stimulants such as caffeine, and a view that cognitive enhancement does not confer new knowledge or understanding. Although a minority of students did view it as cheating, they also expressed strong views, based in part on basic questions of fairness and access. Few students did not have a view either way. These views remained largely unchanged even when presented with considerations of other moderators of the ethics of cognitive enhancement with modafinil.

Modafinil, an atypical CNS stimulant?

Chapter

Nov 2023

Mental Enhancement

Chapter

Full-text available

Jul 2023

Stephan Schleim

This chapter explains how people’s nonmedical substance use, particularly that of prescription stimulants, was understood as “enhancement” or “brain doping” since the early 2000s. In both the academic debate and popular media, it was frequently claimed that ever more people, in particular students, were using such drugs to increase their cognitive performance. This chapter illustrates that this was not a new phenomenon and that even “moral enhancement”, the idea to use substances, and neuroscientific technology to improve people’s moral behavior already existed in the 1960s and 1970s. The actual present prevalence of brain doping is then discussed in detail, with an emphasis on other motives to use drugs besides cognitive enhancement. Indeed, much of the use turns out to be rather emotionally motivated and to cope with stress, particularly in competitive environments, or to be even self-medication of psychological problems. This shows how difficultly the distinction between medical and nonmedical use can be drawn. Finally, nonpharmacological alternatives to improve one’s mental health are presented. The chapter concludes that the academic debate on cognitive enhancement was not very informative and that a general theoretical framework for people’s instrumental substance use should be preferred, which is introduced in Chap. 4 .

Mapping the Mechanisms of Transcranial Alternating Current Stimulation: A Pathway from Network Effects to Cognition

Article

Full-text available

Nov 2014

In recent decades, our appreciation of the complexity of the brain has deepened immensely, as has our understanding of how it performs key functions. In the face of such complexity, and given the rising cost of neuropsychiatric illness (1), an intriguing question is whether we can promote further understanding, and in some cases enhancement, of the typical and atypical brain by targeted modulation of its activity. Notably, transcranial alternating current stimulation (tACS) – which involves transcranial application of weak sinusoidal electrical currents (2) – seems ideally suited to address this question, as it has been demonstrated to modulate endogenous oscillatory electrical activity (3), enhance cognitive functions (4–7), and provide support in neurological disease (8, 9). However, a complete mechanistic pathway between the neuronal and cognitive effects of tACS remains in need of explication, precluding both significant theoretical contribution by tACS studies, and the development of more adaptive neuroenhancement regimes. Therefore, in this Opinion article, we briefly review the role of oscillatory neuronal activity in cognition, before outlining one potential pathway by which the interaction between tACS and endogenous oscillations at a network level may be reconciled with its effects on broader cognitive functions.

Modafinil Increases the Latency of Response in the Hayling Sentence Completion Test in Healthy Volunteers: A Randomised Controlled Trial

Article

Full-text available

Nov 2014
PLOS ONE

Background: Modafinil is a medication licensed for the treatment of narcolepsy. However, it has been reported that healthy individuals without wakefulness disorders are using modafinil off-label to enhance cognitive functioning. Although some studies have reported that modafinil improves cognitive task performance in healthy volunteers, numerous other studies have failed to detect cognitive enhancing effects of modafinil on several well-established neuropsychological tasks. Interestingly, several clinical and preclinical studies have found that improved cognitive task performance by modafinil is accompanied by slower response times. This observation raises the question as to whether this slowing of response time in healthy volunteers is a necessary and sufficient condition for cognitive enhancement with modafinil. The aim of the current experiment was to explore this question by investigating the effects of modafinil on the Hayling Sentence Completion Test (HSCT). Methodology: Sixty-four healthy volunteers received either a single dose (200 mg) of modafinil (n = 32) or placebo (n = 32) in a randomized, double-blind, placebo-controlled, parallel group study in which the principal outcome measures were response latencies on the response initiation and response inhibition sections of the HSCT. Principal findings: Participants dosed with modafinil had significantly longer mean response latencies on the HSCT for both the response initiation and response inhibition compared to participants dosed with placebo. However, participants in both groups made a similar number of errors on each of these measures, indicating that modafinil did not enhance the accuracy of performance of the task relative to placebo. Conclusions: This study demonstrated that administration of single 200 mg doses of modafinil to healthy individuals increased the latency of responses in the performance of the HSCT, a task that is highly sensitive to prefrontal executive function, without enhancing accuracy of performance. This finding may provide important clues to defining the limitations of modafinil as a putative cognitive enhancer. Trial registration: ClinicalTrials.gov NCT02051153.

The regulation of cognitive enhancement devices: Extending the medical model

Article

Full-text available

Mar 2014

This article presents a model for regulating cognitive enhancement devices (CEDs). Recently, it has become very easy for individuals to purchase devices which directly modulate brain function. For example, transcranial direct current stimulators are increasingly being produced and marketed online as devices for cognitive enhancement. Despite posing risks in a similar way to medical devices, devices that do not make any therapeutic claims do not have to meet anything more than basic product safety standards. We present the case for extending existing medical device legislation to cover CEDs. Medical devices and CEDs operate by the same or similar mechanisms and pose the same or similar risks. This fact coupled with the arbitrariness of the line between treatment and enhancement count in favour of regulating these devices in the same way. In arguing for this regulatory model, the paper highlights potential challenges to its implementation, and suggests solutions.

Modafinil Alters Intrinsic Functional Connectivity of the Right Posterior Insula: A Pharmacological Resting State fMRI Study

Article

Full-text available

Sep 2014
PLOS ONE

Background: Modafinil is employed for the treatment of narcolepsy and has also been, off-label, used to treat cognitive dysfunction in neuropsychiatric disorders. In a previous study, we have reported that single dose administration of modafinil in healthy young subjects enhances fluid reasoning and affects resting state activity in the Fronto Parietal Control (FPC) and Dorsal Attention (DAN) networks. No changes were found in the Salience Network (SN), a surprising result as the network is involved in the modulation of emotional and fluid reasoning. The insula is crucial hub of the SN and functionally divided in anterior and posterior subregions. Methodology: Using a seed-based approach, we have now analyzed effects of modafinil on the functional connectivity (FC) of insular subregions. Principal findings: Analysis of FC with resting state fMRI (rs-FMRI) revealed increased FC between the right posterior insula and the putamen, the superior frontal gyrus and the anterior cingulate cortex in the modafinil-treated group. Conclusions: Modafinil is considered a putative cognitive enhancer. The rs-fMRI modifications that we have found are consistent with the drug cognitive enhancing properties and indicate subregional targets of action. Trial registration: ClinicalTrials.gov NCT01684306.

Comparison of pramipexole and modafinil on arousal, autonomic, and endocrine functions in healthy volunteers

Article

Nov 2006
J PSYCHOPHARMACOL

The noradrenergic locus coeruleus is a major wakefulness-promoting nucleus of the brain, which is also involved in the regulation of autonomic and endocrine functions. The activity of the locus coeruleus is believed to be tonically enhanced by a mesocoerulear dopaminergic pathway arising from the ventral tegmental area of the midbrain. Both modafinil, a wakefulness-promoting drug, and pramipexole, a D(2)/D(3)receptor agonist with sedative properties, may act on this pathway, with modafinil increasing and pramipexole decreasing locus coeruleus activity. The aim of this study was to compare the two drugs on alertness, autonomic and endocrine functions in healthy volunteers. Pramipexole (0.5mg), modafinil (200mg), and their combination were administered to 16 healthy males in a double-blind, placebo-controlled design. Methods included tests of alertness (pupillographic sleepiness test, critical flicker fusion frequency, visual analogue scales), autonomic functions (resting pupil diameter, light and darkness reflex responses, heart rate, blood pressure, salivation, core temperature), and endocrine functions (blood concentrations of prolactin, growth hormone, and thyroid stimulating hormone). Data were analysed by ANOVA. Pramipexole reduced alertness, caused pupil dilatation, increased heart rate, reduced prolactin and thyroid stimulating hormone, and increased growth hormone level. Modafinil caused small increases in blood pressure and core temperature, and reduced prolactin levels. The sedative effect of pramipexole and the autonomic effects of modafinil are consistent with altered activity in the mesocoerulear pathway; the pupil dilatation following pramipexole suggests reduced dopaminergic excitation of the Edinger-Westphal nucleus.

Cognitive effects of methylphenidate in healthy volunteers: a review of single dose studies

Article

Jan 2014

Beneficial Effects of Ginkgo biloba in Neurological Disorders

Chapter

Jan 2013

Akhlaq A. Farooqui

Ginkgo biloba (G. biloba), which belongs to the family Ginkgoaceae, is an important herb from the Chinese traditional system of medicine (Huh and Staba 1992). Extract prepared from its leaves has been used in traditional medicine for several hundred years. Major component of patented G. biloba leaves extract is called as EGb761. It was developed by Beaufour-Ipsen Pharma (Paris, France) and Dr. Willmar Schwabe Pharmaceuticals (Karlsruhe, Germany). EGb761 contains glycosides of the flavonols quercetin, isorhamnetin, and kaempferol (24 %); the terpene-lactones bilobalide and ginkgolides A, B and C, M, J, and bilobalide (6 %); and less than 5 ppm ginkgolic acid (Figs. 8.1 and 8.2) (Drieu 1986; DeFeudis and Drieu 2000). Other minor constituents of G. biloba include shikimic, vanillic, ascorbic, p-coumaric acids, steroids (sitosterol and stigmasterol), polyprenols, benzoic acid derivatives, carbohydrates, straight chain hydrocarbons, alcohol, ketones, and 2-hexenol. G. biloba constituents possess potent central nervous system (CNS) activity (Di Renzo 2000 including enhancement of memory, concentration, mental alertness, and decrease in mental fatigue. Many of these constituents produce memory boosting and mental altering effects, which are due to antioxidant- and neurogenesis-promoting properties of flavonols of G. biloba (Fig. 8.3) (Yoo et al. 2011). In addition, G. biloba terpenes are involved in antagonizing platelet activating factor, an endogenous mediator of inflammation and nociception produced by a variety of inflammatory cells, which may improve cardiovascular blood flow (Smith et al. 1996). G. biloba flavonoids have also been reported to dilate blood vessels by increasing the release of endothelium-derived relaxing factor and prostacyclin (PGI2) from vascular endothelial cells and decrease blood viscosity by antagonizing platelet activating factor.

Attention in Cognitive Neuroscience: An Overview

Article

Enhancing cognition using transcranial electrical stimulation

Article

Jun 2015

Piracetam-induced improvement of mental performance

Article

Aug 1976

A double-blind, intra-individual cross-over comparison of the mental performance of 18 aging, non-deteriorated individuals during two 4-week periods of piracetam (1-acetamide-2-pyrrolidone) and placebo administration was performed using conventional and computerized perceptual-motor tasks. In a majority of these tasks the subjects did significantly better when on piracetam than on placebo, a finding consistent with ratings completed by two independent observers. The findings indicate new avenues for the treatment of individuals with reduced mental performance possibly related to disturbed alertness — a neglected group of psychiatric conditions.

Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review

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