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Prepotent response inhibition and reaction times in children with attention

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DOI: 10.1007/s12402-017-0223-z

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ADHD Atten Def Hyp Disord
DOI 10.1007/s12402-017-0223-z

ORIGINAL ARTICLE

Prepotent response inhibition and reaction times in children

with attention deficit/hyperactivity disorder from a Caribbean
community
Giomar Jiménez-Figueroa1 • Carlos Ardila-Duarte1 • David A. Pineda2,3 •
Johan E. Acosta-López1 • Martha L. Cervantes-Henrı́quez1 • Wilmar Pineda-Alhucema1 •
Jeimys Cervantes-Gutiérrez1 • Marisol Quintero-Ibarra1 • Manuel Sánchez-Rojas1 •
Jorge I. Vélez2,4,5 • Pedro J. Puentes-Rozo1,6

Received: 1 March 2016 / Accepted: 16 February 2017

 Springer-Verlag Wien 2017

Abstract Impairment in inhibitory control has been pos-
tulated as an underlying hallmark of attention deficit/hy-
peractivity disorder (ADHD), which can be utilized as a
quantitative trait for genetic studies. Here, we evaluate
whether inhibitory control, measured by simple automa-
tized prepotent response (PR) inhibition variables, is a
robust discriminant function for the diagnosis of ADHD in
children and can be used as an endophenotype for future
genetic studies. One hundred fifty-two school children
(30.9% female, 67.8% with ADHD) were recruited. The
ADHD checklist was used as the screening tool, whilst the
DSM-IV Mini International Neuropsychiatry Interview,
neurologic interview and neurologic examination, and the
WISC III FSIQ test were administered as the gold standard
Giomar Jiménez-Figueroa, Jorge I. Vélez and Pedro J. Puentes-Rozo
have contributed equally to this work and should be considered first
author.
& Pedro J. Puentes-Rozo
ppuentes1@unisimonbolivar.edu.co
1
Grupo de Neurociencias del Caribe, Laboratorio de
Neurociencias Cognitivas, Unidad de Neurociencias
Cognitivas, Universidad Simón Bolı́var, Calle 54 # 59 -189,
Sede 1, Bloque C, Barranquilla, Colombia
2
Neuroscience Research Group, University of Antioquia,
Medellı́n, Colombia
3
Neuropsychology and Conduct Research Group, University
of Antioquia, Medellı́n, Colombia
4
Universidad del Norte, Barranquilla, Colombia
5 2014; Thapar and Cooper 2015). ADHD, which corre-
Genomics and Predictive Medicine Group, John Curtin
School of Medical Research, Australian National University,
Canberra, ACT, Australia
6
Grupo de Neurociencias del Caribe, Universidad Simón
Bolı́var-Universidad del Atlántico, Barranquilla, Colombia
procedure to assert ADHD diagnosis. A Go/No-Go task
using a naturalistic and automatized visual signal was
administered. A linear multifactor model (MANOVA) was
fitted to compare groups including ADHD status, age, and
gender as multiple independent factors. Linear discriminant
analysis and the receiver operating characteristic curve
were used to assess the predictive performance of PR
inhibition variables for ADHD diagnosis. We found that
four variables of prepotent response reaction time- and
prepotent response inhibition established statistically sig-
nificant differences between children with and without
ADHD. Furthermore, these variables generated a strong
discriminant function with a total classification capability
of 73, 84% specificity, 68% sensitivity, and 90% positive
predictive value for ADHD diagnosis, which support
reaction times as a candidate endophenotype that could
potentially be used in future ADHD genetic research.
Keywords Inhibitory control
Prepotent response
inhibition
Reaction time
ADHD
Endophenotypes
Introduction
Attention deficit/hyperactivity disorder (ADHD) is a
childhood-onset neurodevelopmental disorder character-
ized by symptoms of inattention and motor hyperactivity/
impulsivity, some of which appear in the preschool period,
and their difficulties often continue into adulthood
(American Psychiatric Association 1994; Pauli-Pott et al.
sponds to a diagnostic category in the Diagnostic and
Statistical Manual of Mental Disorders 5th edition (DSM-
5) (American Psychiatric Association 2013), is the most
common developmental behavioral disorder with a

123

worldwide prevalence estimation of 5–11% of children
during school age (Pauli-Pott et al. 2014; Pineda et al.
2003; Thapar and Cooper 2015). Although the ADHD
etiology remains controversial, recent research supports
that ADHD and related conditions are determined by
genetic factors that confer susceptibility and therefore drive
the symptoms of the categorical diagnosis with several
comorbidities (i.e., complex phenotype), or genes that are
associated with cognitive or underlying quantitative traits
(i.e., endophenotypes) (Almasy and Blangero 2001; Arcos-
Burgos et al. 2004, 2010, 2012; Castellanos and Tannock
2002; Doyle et al. 2005; Mastronardi et al. 2015). Fur-
thermore, some authors propose that there are symptoms,
especially those related to comorbidities, which could be
explained by major genetic factors, whilst others are caused
by the interaction between environmental factors and
genetic loci. These symptoms may result in severe social
impairment during adolescence and adulthood (Pauli-Pott
et al. 2014; Pineda et al. 2007; Thapar et al. 2003, 2006;
Thapar and Cooper 2015).
Research conducted on cognitive impairment in patients
with ADHD supports the hypothesis of an executive
function deficiency (Doyle et al. 2005; Pauli-Pott et al.
2014; Willcutt et al. 2005). Probably an abnormal action
control and/or a deficient response inhibition could explain
the difficulties of these children to stop impulsive or
ongoing behaviors and controlling interference during tasks
that require high levels of concentration (Bari and Robbins
2013; Barkley 1997; Doyle et al. 2005; Mastronardi et al.
2015; Pauli-Pott et al. 2014). Studies that analyzed quan-
titative and objective discriminant traits in ADHD have
proposed the deficit in the action control or in the inhibitory
control as endophenotypes candidates in ADHD (Acosta
et al. 2013; Aron and Poldrack 2005; Aron et al.
2004, 2014; Castellanos and Tannock 2002; Crosbie and
Schachar 2001; Goos et al. 2009; Puentes 2009; Schachar
et al. 2005).
Inhibitory control is defined as the individual’s ability to
stop a response, which has three basic components: inhi-
bition of the ongoing response, inhibition of the prepotent
response, and inhibition of the interference. Inhibitory
control involves the inhibition of the ongoing response,
which must be given to a specific programmed event, that
is, the retracted response allows a time for taking the
correct decision, or to control the interference from other
automatic or dominant cognitive responses before any final
decision takes place (Aron and Poldrack 2005; Aron et al.
2004, 2014; Bari and Robbins 2013; Barkley 1997; Pauli-
Pott et al. 2014; van der Oord et al. 2012).
Prepotent response (PR) is defined as a dominant
response, which has been previously reinforced in order to
automatize it. Prepotent response inhibition consists in
converting the prepotent response in a mistake or
123
G. Jiménez-Figueroa et al.
ineffective response, changing the correct response into a
new and non-automatized response. Then, the individual
must have the capability to inhibit the prepotent response
and changing it for the new less dominant response. Some
prepotent response tasks have used a naturalistic or realistic
approach, using the socially automatized green (go) and red
(stop) visual signals (Aron and Poldrack 2005; Aron et al.
2004, 2014). These responses have been reinforced from an
early age; they are incorporated into individual’s behav-
ioral repertoire and ensure the implementation of an
automatic response when a situation appears. The use of
these tasks (naturalistic task), over traditional Go/No-Go
task when evaluating inhibition of prepotent response
could give more effective results in the identification of
endophenotypes of ADHD than establish a predominant
response to a specific task.
Barkley (1997) states that the ‘‘primary neuropsycho-
logical dysfunction’’ in ADHD is a deficit in behavior
inhibition and proposes a theoretical model that links
inhibition to four executive functions from which it would
be dependent: ‘‘working memory,’’ ‘‘self-regulation of
affect-motivation-alert,’’ ‘‘internalization of language’’ and
‘‘reconstitution’’ (behavioral analysis and synthesis). This
model postulates that altered inhibition processes would
affect these components and motor control processes.
Specific deficits in any of these functions will produce
relatively different results, indicating that the alteration of
inhibitory control is the fundamental axis that disrupts
execution on the behavioral and emotional levels (espe-
cially manifested in ADHD), which could subsequently
interfere with social and academic activities (Puentes-Rozo
et al. 2014).
Many studies have approached the correlation between
executive functions alteration, frontal lobe dysfunction,
and ADHD diagnosed through the DSM-V (American
Psychiatric Association 2013; Doyle et al. 2005; Mas-
tronardi et al. 2015; Pauli-Pott et al. 2014; Pineda et al.
2007; Swanson et al. 2007; Willcutt et al. 2005). This
correlation assumes a plausible hypothesis of dopamine
fronto-striatal dysfunction. However, some authors have
found that the results of the neuropsychological studies are
contradictory (Pineda et al. 2007; Willcutt et al. 2005). It is
quite possible that standard tests are inadequate to establish
a powerful discriminant classification in order to use them
as endophenotypes, describe the complexity of this syn-
drome, and also identify its underlying mechanisms
(Castellanos and Tannock 2002; Willcutt et al. 2005). For
these reasons, the design of time controlled and automati-
cally scored tasks are necessary to obtain more robust
measures (Aron 2011; Aron and Poldrack 2005; Aron et al.
2004, 2014; Suarez et al. 2013, 2015).
Although some studies use naturalistic tasks of prepo-
tent response and prepotent response inhibition to compare
Prepotent response inhibition and reaction times in children with attention deficit/…
ADHD-affected and control children, it has been admitted
that prepotent response and prepotent response inhibition
are part of the same range of phenomena that are described
as issues related to motor inhibitory control. The influence
of each of these elements may be related to the type of
ADHD or, most likely, to a common specific underlying
deficit, which could explain the heterogeneity of the
complex ADHD phenotype and its comorbidities (Aron
and Poldrack 2005; Aron et al. 2004, 2014; Castellanos and
Tannock 2002; Kühn et al. 2009).
Crosbie and Schachar (2001) analyzed whether the
deficit in inhibitory control, measured by a stop signal task,
was present in a family-based ADHD sample. Fifty-four
children with ADHD aged between 7 and 12 years old who
had a poor or good inhibition (based on the performance of
stop signal task) were evaluated and compared to 26
healthy children (12 males). Family history of ADHD and
measures of neurobiological and psychosocial risk were
compared among the three groups. A logistic regression
analysis was able to establish that families of children with
poor inhibitory control showed higher prevalence of
ADHD (48.1%) than families of children that showed good
inhibition in the initial test (18.5%) or than families of
healthy children (7.7%). The study concluded that the
deficit in inhibitory control was characteristic in familial
ADHD and supports the hypothesis that cognitive labora-
tory tasks of inhibitory control may serve as a quantitative
discriminant trait, which could be use as endophenotype for
genetic analyses.
Epstein et al. (2011) examined the variability of reaction
times in children with and without ADHD, evaluated
whether this variability was different through a variety of
neuropsychological tasks in the two most common sub-
types of ADHD, and whether it was affected by reward and
event rate manipulation. Fifty-one children with combined
ADHD, 53 with predominantly inattentive ADHD and 47
controls were evaluated using five neuropsychological
tasks (choice and discrimination, child attentional network,
Go/No-Go, stop signal task, and N-back), each of which
allowed to measure reaction times. Multiple indicators of
reaction time variability (i.e., the standard deviation, the
coefficient of variation and ex-Gaussian tau) were used.
Children with ADHD showed greater reaction time vari-
ability than the control group in all five tasks, with not
statistically significant differences in reaction time vari-
ability across ADHD types. Both ADHD groups had lower
scores than control children on all tasks except for the
choice discrimination task. Although the event rate and
manipulation with reward affected reaction time variability
and precision of task scores in general, such manipulations
did not affect the differences between ADHD and control
children. The reaction time variability and accuracy of
work were highly correlated across tasks. Elimination of
variance owing to reaction time variability from the pre-
cision of work did not affect the differences between
groups on the accuracy of the task. This study confirms that
a high reaction time variability is a ubiquitous and strong
phenomenon in both ADHD groups and supports the role
of reaction time and reaction time variability as other
quantitative traits potentially related to ADHD that might
explain its symptoms and some comorbidities (Crosbie
et al. 2013; Klein et al. 2006; Kofler et al. 2013; McAuley
et al. 2014; Tamm et al. 2012; Thissen et al. 2014; Uebel
et al. 2010; Vaurio et al. 2009).
There is now consensus that alterations in inhibitory
control are directly related to clinical manifestations of
ADHD (Bhaijiwala et al. 2014; Crosbie and Schachar
2001; Goos et al. 2009; Pani et al. 2013; Wodka et al.
2008). Nevertheless, despite the extensive research con-
ducted on this issue, there are just few studies analyzing a
visual naturalistic signal prepotent response task and its
contribution to ADHD symptoms (Aron and Poldrack
2005; Aron et al. 2004, 2014). Here, we hypothesized that a
low score on a visual naturalistic signal prepotent response
task, as well as reaction time and reaction time variability
in this task, are powerful measures that could be used as
quantitative traits (endophenotype candidates) in the study
of familial ADHD. The use of these (naturalistic) tasks
over a traditional Go/No-Go task when evaluating inhibi-
tion of prepotent response could give more effective results
in the identification of ADHD endophenotypes and to
differentiate ADHD-affected individuals than a predomi-
nant response to a specific task.
Subjects and methods
Participants
In order to identify and recruit nuclear families with
ADHD, 845 ADHD checklist questionnaires (Pineda et al.
1999a, b) were administered as screening tool to parents
and teachers of students from 1st to 6th grades (ages
6–11 years old), from different schools in Barranquilla,
Colombia and of medium socio-economic stratum
(monthly household income of *$2000 to *$4000).
Barranquilla is a modern city with a population of *1.2
million people placed in the Atlantic north coast of
Colombia. Culturally, people behave as a typical Caribbean
community, which have been constituted by periodic
waves of internal and external immigrants (Villalón 2008).
This community has predominantly mix ethnicity (racial
intermix between white European [Andalusian-Spanish],
black African, Syrian-Lebanese [Arabian], Jewish, and
Amerindian people) (Barragán-Duarte 2007), which differs
from the Colombian Andean ‘‘paisa’’ community
123

Table 1 Demographic and
Control (n = 49)
intellectual characteristics of
Means (SD)
152 school children, aged
6–11 years old, from Age 8.84 (1.54)
Barranquilla-Colombia
Wechsler FSIQ 107.37 (12.91)
Gender n (%)
Male/female 32/17 (65.3/34.7)
SD standard deviation
a
Student’s t for continuous variables and v2 for categorical variables. Statistically significant differences
are shown in bold
previously described as a genetic isolate with a high
prevalence (11–15%) of ADHD (Arcos-Burgos et al.
2002, 2004).
One hundred and fifty-two school children, 103 (67.8%)
affected with ADHD (72 of them were combined- and 31
inattentive-type) and 49 unaffected (controls), were included
in this study. Given that out of the 845 screened children, 103
were identified as having ADHD (72 of them were ADHD-
combined type and 31 were ADHD inattentive), and the
percentage of ADHD in this sample was 12.2 (i.e., the like-
lihood of observing a child with ADHD in our sample was 12
in 100). The Spanish version of the DSM-IV Mini Interna-
tional Neuropsychiatry Interview was administered to the
parents of this sample by trained neuropsychologist as the
gold standard diagnostic tool (Sheehan et al. 1998) so chil-
dren were accordingly diagnosed with the combined and
predominantly inattentive ADHD type. In order to exclude
major neurologic diseases (moderate to severe traumatic
brain injury, CNS infections, epilepsy, infantile cerebral
palsy, and perceptual impairments, and pervasive develop-
mental disorders), a certificated neurologist and neurosur-
geon performed the neurologic interview and the neurologic
examination to parents. Similarly, certificated psychologists
and neuropsychologists administered the Wechsler Intelli-
gence Scale for Children (WISC) (Wechsler 2006) Spanish
version III (WISC III) to discard mental retardation. All the
assessment procedures were supervised and discussed in our
team by a certified Behavioral Neurologist.
Only children that were (1) Spanish native speakers, (2)
aged 6–11 years old, (3) attend a school of the medium
socio-economic stratum of Barranquilla, Colombia, (4) had
both parents alive (meet nuclear families), (5) their parents
and teachers completed the screening ADHD checklist
(screening test), (6) had WISC III FSIQ score C70, and (7)
both parents accept to participate by signing the informed
consent and attending to the neuropsychiatry, neurologic,
psychological, and controlled cognitive assessments, were
included in this study. Children with clinical history of any
major neurologic disease (moderate or severe traumatic
brain injury, infantile cerebral palsy, epilepsy, meningitis
or encephalitis, non-corrected visual or auditory impair-
ment [including color blindness]) and/or pervasive
123
G. Jiménez-Figueroa et al.
ADHD (n = 103) Statistic indexa P value
Means (SD)
7.75 (1.46) 4.205 0.001
104.83 (17.54) 0.900 0.369
n (%)
73/30 (70.9/29.1) 0.482 0.488
developmental disorders or psychotic disorders were
excluded. This research was approved by the ethical
committee of the Simón Bolı́var University of Barran-
quilla, Colombia, and was funded by a grant from the
Colombian Institute of Science and Technology (COL-
CIENCIAS) to study the ADHD complex phenotype and
cognitive endophenotypes related to major or susceptibility
genes. Demographic and intellectual characteristics of the
sample are described in Table 1.
Procedure
The ADHD checklist questionnaire (Pineda et al. 1999a, b)
was applied to all students (n = 845) from 1st to 6th grades
attending a medium socio-economic stratum public school
in Barranquilla, Colombia. Participants with a T score C60
in the ADHD checklist were selected as probable ADHD
probands, whilst those with T scores B55 were recruited as
probable controls (Pineda et al. 1999b). Parents and chil-
dren were later contacted for the administration of psy-
chiatric and neurologic assessment. ADHD diagnosis was
confirmed by the M.I.N.I-Child (Sheehan et al. 1998)
structured neuropsychiatric interview. Participants were
classified as control (unaffected), combined- and inatten-
tive-type ADHD-affected groups. Mental retardation was
ruled out using WISC III intelligence scale. Children who
met the inclusion criteria (see above) performed a Go/No-
Go task at the Laboratory of Cognitive Neuroscience of
Universidad Simón Bolı́var, Barranquilla.
Clinical Questionnaires
ADHD Checklist Screening Questionnaire
This brief scale takes the symptoms of the criterion A of
DSM-V (American Psychiatric Association 2013), scoring
from 0 (never) to 3 (almost always). Validation studies in
Colombia have found strong internal consistency (Cron-
bach’s a coefficient of 0.71–0.92) and a stable structure of
two factors: inattention and hyperactivity/impulsivity
(Pineda et al. 1999b). This instrument has been validated
for use in Spanish-speaking populations and has been used
Prepotent response inhibition and reaction times in children with attention deficit/…
in Colombia to estimate the prevalence of ADHD in
Antioquia and Caldas (Pineda et al. 1999a, 2003).
Gold standard procedures
Structured Psychiatric Interview
The Mini International Neuropsychiatry Interview for
children (M.I.N.I-Child) (Sheehan et al. 1998) is an
instrument designed as an assistant tool to make diagnos-
tics under to the DSM-V (American Psychiatric Associa-
tion 2013) or ICD 10 (World Health Organization) systems
in both the daily clinical practice and in research. The
current Spanish version of the M.I.N.I.-Child (version 4.6)
was used in a standardized manner. It was administered to
both parents in one session of *45 min, and a categorical
diagnostic of healthy children (control), ADHD, ADHD
types, comorbidities and exclusion diagnoses were recor-
ded (Ferrando et al. 1997).
Structured neurologic interview and examination
A previously used (Arcos-Burgos et al. 2002; Palacio et al.
2004; Jain et al. 2006) structured neurologic interview was
utilized to ascertain ADHD gold standard diagnosis, which
need to exclude any major neurologic disease that could
better explain the symptoms (DSM-V ADHD criterion E).
This interview was administered to both parents in one
session of 15 min. A physical and neurologic examination
was performed in one 15-min session to children who had
no history of any neurologic disease according to parents.
All selected children had normal general and neurologic
assessment.
WISC III for Intellectual Assessment
Intellectual level was assessed with WISC Spanish version
III. In order to exclude children with mental retardation, the
Full-Scale Intelligence Quotient (FSIQ) calculated and
children with a FSIQ score \70 were excluded (Wechsler
2006). All included children in our sample had FISQ
score C70.
Cognitive assessment: the visual signal PR-RT
and Go/No-Go tasks
A Go/No-Go task, using an automatically scored natural-
istic visual signal prepotent response, reaction time and
reaction time variability, was administered by a trained
Neuropsychologist to the selected children, which included
two parts: Part A, using and automating the prepotent
response, consisted of 50 randomized trials, with 2000 ms
of duration and 1000 ms interstimulus interval,
automatically balanced, with a usual Go/No-Go naturalistic
dominant stimuli (green [go] and red [stop] signals). Each
child had to respond to the social automatized go signal
(green light) and had to stop the response to the known no-
go signal (red light). These signals are familiar to people
since preschool period, when the colors are introduced, as
they are used worldwide to show when to continue or stop
any kind of action. Part B, which corresponds to prepotent
response inhibition performance, consisted of 50 trials of
reversal Go/No-Go stimuli (red [go] and green [stop] sig-
nals) with the same randomized and automatically scored
conditions of Part A. The go signal was changed to red
light and the no-go or stop signal was change to green
light. Reaction times for prepotent response (PR–RT),
prepotent response inhibition (PRI–RT), variability for
prepotent response (PR–RTV), variability for prepotent
response inhibition (PRI–RTV), omission (non-response to
go signal), commission (to response to stop signal), PR
false anticipation (PRFA), and PRI false anticipation
(PRIFA) errors (to response during 1 s with a black screen
interval), were obtained and recorded for each participant.
A multi-operational apparatus for reaction times (MOART)
system model 35600, with PsymSoft II Psychomotor
Control Software model 35800, was used. This system
allows us to perform Go/No-Go tasks and automatically
scoring children’s performance. In both Part A and Part B,
the ratio of Go/No-Go trials was 50%.
A controlled Go/No-Go was performed in the morning
between 8 and 11 am, in a light-, temperature-, and noise-
controlled environment. Children were trained in a RT test
with a Go/No-Go task consisting of moving the index
finger of the dominant hand from a starting point (C0) to a
target point (C5), and back to C0 in an away/toward-the-
body fashion. Each child was familiarized with the
equipment and Go/No-Go task, preliminary testing, and
established the accomplishment of five correct alternate
Go/No-Go responses in order to guarantee a correct green-
and-red color recognition, and the comprehension of the
Go/No-Go task.
Statistical analysis
For statistical analyses, the Statistical Package for Social
Sciences (SPSS) version 17 and R version 3.3.0 (http://
www.r-project.org). A descriptive analysis of all variables
was conducted. The average age, education, number of
control and ADHD children and percentages according to
the study variables were established. To compare ADHD-
affected and control children, a t test was used for demo-
graphic continuous variables, and a v2-based test was used
for categorical variables. Normality of quantitative vari-
ables was assessed using a Kolmogorov–Smirnov’s test. A
linear stepwise backward multifactor model and
123
 G. Jiménez-Figueroa et al.

Table 2 Comparison of PR and

Control ADHD Statistic adj. F P value
RT variables between control
Mean (SD) Mean (SD)
and ADHD-affected group after
age and gender are controlled PR–RT 508.6 (129.0) 664.80 (147.50) 16.742 <0.001
for and Bonferroni’s multiple
testing correction is used PR–RTV 153.8 (88.6) 251.09 (134.39) 9.179 0.003
PR omission errors 0.35 (1.12) 0.35 (1.13) 0.662 0.417
PR commission errors 1.5 (1.6) 2.03 (1.94) 2.403 0.04
PRFA 1.5 (2.2) 1.47 (2.21) 3.365 0.069
PRI–RT 511.6 (126.7) 650.41 (141.27) 12.947 <0.001
PRI–RTV 149.7 (79.9) 251.21 (121.89) 13.035 <0.001
PRI omissions errors 0.18 (0.53) 0.65 (1.21) 3.071 0.012
PRI commissions errors 1.94 (2.70) 2.44 (2.17) 1.880 0.173
PRIFA 2.90 (4.22) 5.01 (4.88) 2.094 0.150
Statistically significant differences are shown in bold
SD standard deviation, PR prepotent response, PRI prepotent response inhibition, RT reaction time (ms),
RTV reaction variability, PRFA prepotent response false anticipation, PRIFA prepotent response inhibition
false anticipation

multivariate analysis of variance (MANOVA) with Bon-
ferroni’s correction (Vélez et al. 2014) for multiple testing
were used to compare two groups, with ADHD status, age,
and gender as multiple independent factors assuming that
PR, PRI–RT, omission–commission, and PRFA–PRIFA
errors are multiple dependent factors. Analysis of variance
(ANOVA) was used to compare quantitative demographic
variables among ADHD groups (control, combined and
inattentive types); a v2 distribution was utilized to compare
gender proportion among the three groups. Comparisons
among the control and the two ADHD types were also
performed in order to establish whether these groups dif-
fered in PR and PR–RT performances when compared to
the control group, and between them. Tukey’s post hoc
analyses were used. Assuming that variables showing sta-
tistically significant differences between the ADHD and
control groups after controlling for age, gender, and
ADHD-type effect could be ascertained as quantitative
underlying traits specific to ADHD, a correlation matrix
was computed and a discriminant analysis was performed
using ADHD status as outcome (control vs. affected) and
PR-RT, PRI–RT, PR–RTV, and PRI–RTV as the inde-
pendent factors. Finally, a receiver operating characteris-
tics (ROC) curve with the derived discriminant function
was constructed, and the correct classification rate, sensi-
tivity, specificity as well as other meaningful performance
measures were computed.
Results
Table 1 describes demographic and intellectual compar-
ison between control and unified ADHD-affected cases.
Although there were statistically significant differences
between age groups, the FSIQ was not significantly dif-
ferent between children with and without ADHD, and
gender proportions were similar.
The PR–RT was statistically significantly longer in
children with ADHD than in controls. This difference
holds after controlling for gender and age, and after
Bonferroni’s correction for multiple testing. A similar
result was observed for PR–RTV. In particular, the inhi-
bition of PR–RT was longer in children with ADHD than
in controls, with wider variability in the former group.
This latter finding was statistically significant after con-
trolling for gender and age, and correction for multiple
testing using Bonferroni’s method. On other hand, PR
commission and PRI omissions errors showed statistically
significant differences between children with and without
ADHD after controlling for age in the multivariate model,
with more omission errors in the ADHD group (see
Table 2). In the PRI task, however, ADHD children did
not make more errors than healthy control children
(Table 2). Interestingly, PR–RT and PR–RTV, PR–RT
and omission errors, and PR–RTV and omission errors
were found to be statistically significantly correlated in
Part A of the Go/No-Go task (Fig. 1a). Furthermore, PRI–
RT and PRI–RTV, and PRI–RT and omission errors, and
PRI–RTV and omission errors were correlated in Part B
of the Go/No-Go task (Fig. 1b). Likewise, PR–RTV and
PRI–RTV were found to be statistically significantly
correlated with commission errors in Part B of the Go/No-
Go task (Fig. 1b).
Out of the 152 children included in this study, 72
(47.4%) met the criteria for the ADHD-combined type
(20.8% females), 31 (20.4%) were classified as ADHD
inattentive (48.4% females) and 49 (32.2%) were controls
(34.7% females) (see Table 3). The control group was

123
Prepotent response inhibition and reaction times in children with attention deficit/…

200 400 600 800 0 2 4 6 8 10 12 200 400 600 800 0 2 4 6 8 10 12

1200 1200
a 0
PR.RT 1
2
1000 * * 1000

800

600
PR.RT 0.60 0.083
0.39
800

600

400 400

800 PR.RTV 800

*
600 600
PR.RTV 0.23 0.33
400 400

200 200

8
COMISSION.A 8

6 6

4
COMISSION.A 0.12
4

2 2

0 0

12 12

10 OMISSION.A 10

8 8

6 6 OMISSION.A
4 4

2 2

0 0

400 600 800 1000 0 2 4 6 8 400 600 800 1000 0 2 4 6 8

200 400 600 800 0 1 2 3 4 5 200 400 600 800 0 1 2 3 4 5

b PRI.RT
0
1
1000
* * *
1000

2
800 800

600
PRI.RT 0.73 0.24 0.37
600

400 400

800 PRI.RTV 800

* *
600 600

400 400
PRI.RTV 0.35 0.36
200 200

12 12
COMISSION.B 10 10
8 8
6 COMISSION.B 0.21 6
4 4
2 2
0 0

5 5

4 OMISSION.B 4

3 3

2 2
OMISSION.B
1 1

0 0

400 600 800 1000 0 2 4 6 8 10 400 600 800 1000 0 2 4 6 8 10

Fig. 1 Correlation matrices for the a Part A and b Part B of the Go/ left panel. Correlations with p \ 0.05 are marked with a asterisk
No-Go task. Black, red and green symbols correspond, respectively, symbol in the right panel
to healthy, ADHD-combined and ADHD-inattentive children in the

slightly older than the ADHD-combined and ADHD-inat- (Table 4). Tukey’s post hoc analysis showed that the average
tentive groups (p = 0.002, Table 3). No statistically sig- values of the above scores differed between ADHD-com-
nificant difference was found in the average FSIQ score bined and ADHD-inattentive individuals (see Table 4).
across the three groups. Interestingly, the proportion of Furthermore, the control and ADHD-combined-type group
females in the ADHD-inattentive group was statistically statistically differed in the average PRFA, PRI omissions and
higher than that of the ADHD-combined and control PRIFA scores according to a multivariate stepwise model
groups (see Table 3). (see Table 4). Close inspection revealed that, whilst the
We found that PR–RT, PRI–RT, PR–RTV, and PRI–RTV difference in PRIFA could be explained by either ADHD
scores were statistically different between the ADHD and status or gender, age might be responsible for the difference
control groups after adjusting by age and gender, and con- in the remaining two variables (Table 4). The fact that
trolling for multiple testing using Bonferroni’s method pairwise comparison between the combined and inattentive

123
 G. Jiménez-Figueroa et al.

Table 3 Comparison of demographic and intellectual variables among control group and ADHD-combined and inattentive subtypes
Control (0) ADHD ADHD Statistic indexa P valueb Significant differences
n = 49 Combined (1) Inattentive (2) group pairs
Mean (SD) n = 72 n = 31
Mean (SD) Mean (SD)

Age 8.84 (1.55) 7.50 (1.40) 8.40 (1.50) 5.255 0.002 0–1c
1–2c
Wechsler FSIQ 107.37 (12.91) 105.10 (17.30) 104.30 (18.40) 0.431 0.651
Gender n (%) n (%) n (%)
Male/female 32/17 57/15 16/15 8.184 0.02 0–1
(65.3/34.7) (79.2/20.8) (51.6/48.4) 1–2
Statistically significant differences are shown in bold
SD standard deviation
a
F statistic from ANOVA for Age and Wechsler FSIQ, and v2 for gender
b
Based on a Tukey’s post hoc analyses for ADHD group pairs
c
Statistically significant at p \ 0.05 using Tukey’s least significant difference

Table 4 Comparison of PR and RT variables among control group and ADHD-combined and inattentive subtypes after age and gender are
controlled for and Bonferroni’s multiple testing correction is used
Variable Control (0) ADHD ADHD Statistic P value Significant differences
n = 49 Combined (1) Inattentive (2) adj. F group pairs
Mean (SD) n = 72 n = 31
Mean (SD) Mean (SD)

PR–RT 508.6 (129.0) 661.6 (146.0) 672.0 (153.0) 9.532 0.001 0–1
0–2
PR–RTV 153.8 (88.6) 256.0 (139.5) 239.7 (123.2) 4.922 0.006 0–1
0–2
PR omission errors 0.35 (1.12) 0.68 (1.16) 1.2 (2.9) 1.94 0.06 NS
PR commission errors 1.5 (1.6) 2.2 (2.1) 1.7 (1.6) 0.050 0.108 NS
PRFA 1.5 (2.2) 3.5 (3.3) 1.7 (1.9) 8.337 0.001 0–1a
1–2
PRI–RT 511.6 (126.7) 650.1 (145.2) 651.0 (134.0) 9.819 0.001 0–1
0–2
PRI–RTV 149.7 (79.9) 261.0 (132.0) 228.5 (92.2) 8.553 0.001 0–1
0–2
PRI omissions errors 0.18 (0.53) 0.72 (1.15) 0.48 (0.96) 5.026 0.003 0–1a
PRI commissions errors 1.94 (2.70) 2.40 (2.10) 2.50 (2.40) 1.849 0.506 NS
PRIFA 2.90 (4.22) 5.32 (5.10) 4.30 (4.50) 3.972 0.01 0–1a
SD standard deviation, PR prepotent response, PRI prepotent response inhibition, RT reaction time (ms), RTV reaction time variability, PRFA
prepotent response false anticipation, PRIFA prepotent response inhibition false anticipation, NS not statistically significant at 5%
a
Statistically significant at p \ 0.05 using Tukey’s least significant difference

groups shows that PRIFA is different, and suggests the for-
mer group is ‘‘more impulsive’’ than the latter.
The discriminant function derived using discriminant
analysis has an area under the curve of 0.73 (95% CI
0.66–0.79) and correctly classifies 73% (95% CI 66–80%)
of individuals in the total sample, 84% (74–93%) of ADHD
subjects (specificity) and 68% (95% CI 60–80%) of con-
trols (sensitivity) (Table 5). The likelihood positive ratio of
this function is 4.16, suggesting that children with ADHD
are *4 times more likely to have a positive diagnosis than
unaffected children when the PR–RT derived discriminant
score is used. Furthermore, the estimated odds ratio (OR)
of *11 (95% CI 4.3–28.5) indicates that using this dis-
criminant score participants are *11 times more likely to
be classified as having ADHD than as a control (see
Table 6).

123
Prepotent response inhibition and reaction times in children with attention deficit/…

Table 5 Discriminant analysis for ADHD groups response to such stimuli is a powerful ADHD mark—this
Variable Wilks’ k F P value
assumption was first postulated by Barkley (1997) and
more recently confirmed by Bhaijiwala et al. (2014). In
PR–RT 0.788 40.245 0.001 fact, this type of Go/No-Go task that is intuitively learned
PR–RT variability 0.876 21.240 0.001 could be a very simple activity to measure executive
PR inhibition–RT 0.814 34.200 0.001 control. Hence, lengthening of observed RT for PR per-
PR inhibition–RT variability 0.842 28.153 0.001 formance would indicate a very severe weakness in the
Four variables showed statistically significant differences between inhibitory control in ADHD children, primarily for
groups after age, gender, and ADHD type were controlled for retroactive response control (Aron and Poldrack 2005;
One discriminant function, Wilks’ k = 0.752; v2 = 42.126; Aron et al. 2004, 2014; Pani et al. 2013).
p \ 0.001. A correct classification rate of 73% (95% CI 66–80%), As described in detail by Epstein et al. (2011), some
and ADHD correct classification of 84% (74–93%) and a control measures of RTV have shown to be statistically signifi-
correct classification 68% (95% CI 60–80%) were achieved
cantly wider in ADHD children than in controls. In our
study only the average variability of PR–RT scores was
Table 6 Receiver operating characteristic of the derived discriminant measured throughout the trials. This direct score of the PR–
function for ADHD diagnosis RTV, without any additional statistical processing, in
Performance measure Value 95% Confidence interval
contrast with the automatized and simplistic nature of the
Go/No-Go task suggested by Epstein et al. (2011), showed
AUC 0.73 0.66–0.79a statistically significant differences between ADHD and
Sensitivity 0.68 0.60–0.80 control children after adjusting by age and gender in a
Specificity 0.84 0.74–0.93 multivariate model. This finding produces an additional
Prevalence detection 0.68 0.61–0.74 quantitative measure to support the hypothesis of a severe
Predictive positive value 0.90 – inhibitory control dysfunction related to ADHD (Bhaiji-
Predictive negative value 0.55 – wala et al. 2014; Crosbie and Schachar 2001; Goos et al.
LR positive 4.16 – 2009; Hervey et al. 2006; Klotz et al. 2012; Pani et al.
LR negative 0.38 – 2013).
Odd ratio 10.9 4.3–28.5 Measures on PRI-RT and PRI-RTV obtained during part
Relative risk 2.1 1.5–2.6 B of the Go/No-Go task (see Methods) only confirmed the
previous findings described above: that children with
LR likelihood ratio
a ADHD had poorer performance than controls after the
Based on B = 20,000 nonparametric bootstrap samples
effects of age and gender were controlled for. As conse-
quence, another two quantitative variables were derived as
Discussion evidence of the executive control deficiency in ADHD
(Barkley 1997; Doyle et al. 2005; Berwid et al. 2014;
Data on this study showed that ADHD-affected individuals Mastronardi et al. 2015; Pauli-Pott et al. 2014).
had significantly longer PR–RT than unaffected children The PR-based variables identified here (i.e., PR-RT, PR-
after the effect of age and gender was controlled for. This RTV, PRI-RT, and PRI-RTV) were used in a predictive
implies that ADHD children need longer time to process setting to determine their potential for discriminating
adequately the well-known signal to respond (Go) and the ADHD-affected individuals from healthy controls. A linear
automatized signal to stop (No-Go), and strongly suggests discriminant analysis showed that there was a single sta-
that the extended hypothesis, which postulate an IC defi- tistically significant discriminant function; this function
ciency as an underlying EF disorder, should not be rejected correctly classified 73% of children in our sample regard-
(Barkley 1997; Doyle et al. 2005; Mastronardi et al. 2015; less of their ADHD status (Table 5), 84% of children with
Pauli-Pott et al. 2014; Wodka et al. 2008). Empirical evi- ADHD and a positive predictive value of 90% (Table 6).
dence also confirms the slowness of the action control as a Overall, these results suggest that the four intruded vari-
salient hallmark of ADHD throughout the life of affected ables of the derived discriminant function could potentially
individuals (Aron and Poldrack 2005; Aron et al. be used as quantitative ADHD traits (that is, endopheno-
2004, 2014; Bhaijiwala et al. 2014; Crosbie and Schachar types) (Almasy and Blangero 2001; Arcos-Burgos et al.
2001; Goos et al. 2009; Pani et al. 2013). 2004, 2012; Castellanos and Tannock 2002; Doyle et al.
Given the nature of the socially known and repetitively 2005; Mastronardi et al. 2015; Pineda et al. 2011) for
reinforced visual stimuli (usually associated with color futures genetic studies with samples coming from nuclear
learning from preschool), and based on the highly signifi- families, or to study of gene 9 gene and gene 9 envi-
cant results exposed above, it can be assumed that the ronment interactions as an etiologic explanation of ADHD

123

and its comorbidities (Pauli-Pott et al. 2014; Pineda et al.
2007; Thapar et al. 2003, 2006; Thapar and Cooper 2015).
The choose intentional control, measured by delayed
reward, has been studied with the classical marshmallow
experiment, in which children can choose an immediate
reward for one or a delayed reward for two marshmallows
(Mischel et al. 1989). Derived from this model of inhibi-
tory control, a rolling marble white/red Go/No-Go task
with and without reward has been developed in order to
create a prepotent response task (Freeman and Aron 2016;
Kühn et al. 2009) as well as other models to evaluate the
influence of reward in inhibitory control (Desman et al.
2008). A study tested the neural correlates associated with
responding to a rolling marble versus inhibiting a prepotent
response to a rolling marble using a white/red Go/No-Go
task and functional MRI to observe simultaneous regional
activation in the brain. As predicted, children and adults
showed different recruitment of the fronto-basal ganglia
network during intentional inhibition (Schel et al. 2014a;
b). This brain circuitry has been described to be function-
ally altered in people with ADHD in different studies
(Arcos-Burgos et al. 2012; Hwang et al. 2015; Ortiz et al.
2015; Park et al. 2015; Pastura et al. 2015; Salavert et al.
2015; Wilbertz et al. 2015), and has been related to some
candidate and susceptibility genes for ADHD in multi-
generational families from a genetic isolate (Arcos-Burgos
et al. 2012). The findings presented here will allow
researchers to use these quantitative and objective variables
as endophenotypes in future genetic studies.
On the other hand, to determine whether the inhibitory
control deficiency (measured PR–RT and PRI–RT perfor-
mances as part of a complete action control) is related to
either a perceptual deficiency, attentional inhibition control
deficiency, a retrospective and prospective inhibitory con-
trol, to the speed cognitive processing, or to a motor
response control, would require the design of other tasks.
These tasks should include not only randomized natural-
istic automatized Go/No-Go task, but a Go/No-Go task
using different kinds of block designs, black/red marbles
with or without reward, and more neutral stimuli tasks,
which may allow concurrent validation (Alderson et al.
2012; Aron and Poldrack 2005; Aron et al. 2004, 2014;
Bhaijiwala et al. 2014). Because perceptual signal identi-
fication supposes to be socially automatized, our findings
suggest an attentional control deficiency with a longer
speed processing in order to get a good accuracy of the
inhibitory control performance.
Accuracy in inhibitory control would appear to be
similar between the control and ADHD groups mainly
because PR commission and PRI omission errors showed
marginally significant differences with a poorer perfor-
mance in the ADHD group, which was better explained by
age. It could be affirmed that accuracy in PR-RT in
123
G. Jiménez-Figueroa et al.
automatized naturalistic Go/No-Go task would be
explained by changes in developmental inhibitory control
(Aron and Poldrack 2005; Aron et al. 2004, 2014; Bhaiji-
wala et al. 2014; Crosbie and Schachar 2001; Goos et al.
2009; Pani et al. 2013). Future research with preschool-
aged children and adolescents should be considered in
order to resolve this issue.
In order to clarify the aforementioned issue, the ADHD
sample was divided in combined and inattentive types.
Further, multivariate analyses and Tukey’s post hoc pair-
wise comparisons were used and disclosed that the ADHD-
type influences the results. In particular, Tukey’s post hoc
indicated that the control group clearly deviates from both
ADHD groups regarding inhibitory control reaction time,
but the latter groups collapsed in one group in pairwise
analyses of the same variable. This confirmed that the four
PR-RT variables are a hallmark of ADHD condition and
does not depend on ADHD type. On the contrary, inhibi-
tory control impulsive proactive measures by PRFA were
indistinctly explained by age and belonging to the ADHD-
combined group, which splits as part of the ADHD-inat-
tentive group or under scored in a separated subgroup
according the Tukey’s post hoc pairwise comparisons.
Another kind of impulsiveness, measured by PRIFA,
appears to be explained by age, with the poorest score
registered by the youngest children. The significantly lower
inhibitory control performance in the inattentive group,
measured by PRI omissions errors, was also explained by
age. These confounding results could be attributable to the
simplicity and automatizing characteristics of the used Go/
No-Go task. It is possible that a distinct more complex
designed task, like black/red marbles with or without
reward, or using a block design task with more neutral
stimuli, should rule out the influence of age and clearly
establish the lifelong inattentive and impulsive hallmarks
of ADHD diagnosis (Bhaijiwala et al. 2014; Crosbie and
Schachar 2001; Goos et al. 2009; Pani et al. 2013).
Some accepted limitations which affected the robustness
of the presented results are the difficulty to obtain age and
gender balanced sample when ADHD cases were obtained
by screening approach from the general population, and the
simplicity and automatized Go/No-Go task hindered the
clear observation of the inattentive and impulsivity char-
acteristics of the ADHD sample. Furthermore, the cogni-
tive task is somewhat unusual in that the primary measure
for the Go/No-Go task is not the percentage of No-Go trials
on which the subject fails to inhibit their response but
rather the RT for the reversed contingency Go response (go
for red; inhibit for green).
In conclusion, we obtained four robust PR–PRI–RT
variables with strong discriminant capability for ADHD
diagnosis, using a simple automatized task of Go/No-Go
task. Although our data suggest some support that the
Prepotent response inhibition and reaction times in children with attention deficit/…
cognitive paradigm can distinguish ADHD from non-ADHD
children, it will be for other studies to establish whether
there are familial influences on the task (i.e., heritability
analysis). On the other hand, some confounding results were
derived from inattention and impulsivity measures, related
to age and ADHD-type status, which could be originated
from the simplicity of the Go/No-Go task.
Acknowledgements We express our highest appreciation to all
families enrolled in this study. This study was financed by COL-
CIENCIAS, project ‘‘Fenotipos Complejos y Endofenotipos del
Trastorno por Déficit de Atención e Hiperactividad y su Asociación
con Genes Mayores y de Susceptibilidad,’’ Grant 1253-5453-1644,
Contract RC 384-2011. The sponsor of the study has no role in the
study design, data collection, data analysis, data interpretation, or
writing of the paper. JIV thanks Dr. Fernando Marmolejo-Ramos
from The University of Adelaide, Australia, for his advice and
stimulant conversations on reaction times. GJF, JIV, and PJPR have
full access to all the data in the study, and responsible for submitting
this work for publication. The authors assert that all procedures
contributing to this work have been performed in accordance with the
ethical standards laid down in the 1964 Declaration of Helsinki and its
later amendments. The views and opinions expressed in this article
are those of the authors and should not be construed to represent the
views of any of the sponsoring organizations, agencies, or
governments.
Compliance with ethical standards
Ethical standard None of the authors of this paper has a financial or
personal relationship with other people or organizations that could
inappropriately influence or bias the content of the paper. All indi-
viduals participated voluntarily, and provided informed written con-
sent was obtained from all participants either directly or from their
parents (in the case of children; \18 years old). This study was
approved by The Ethics Committee of Universidad Simón Bolı́var at
Barranquilla, Colombia (Approval # 00032 of October 13, 2011).
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