Social and executive functioning in individuals with autism spectrum disorder without intellectual disability: The case-control study protocol of the CNeSA study

Abstract

Several studies suggest that children and adolescents with autism spectrum disorder (ASD) often present deficits in executive functions (EFs). The research on cold EF shows a high heterogeneity across different cohorts of patients as well as different study designs, while studies investigating hot EF and their relationship with different ASD phenotypes are still limited and related only to specific domains, although this concept could contribute to clarify the phenotypical variability by explaining the difficulties encountered by individuals with ASD in daily life, where stimuli are often emotionally charged. With the aim to identify specific neuropsychological profiles in children and adolescents with ASD without intellectual disability, we designed a study protocol comparing a clinical sample of individuals with ASD to aged-matched (10–17 years) typically developing controls (TDC) on a neuropsychological test battery investigating both “cold” and “hot” EF with the purpose of further investigating their relationships with ASD symptoms. Autonomic measures including heart rate, heart rate variability, skin conductance, and salivary cortisol were also recorded before/during/after the neuropsychological testing session. This paper describes the case–control study protocol named “ Caratterizzazione NEuropsicologica del disturbo dello Spettro Autistico, senza Disabilità Intellettiva, CNeSA study ,” its rationale, the specific outcome measures, and their implications for the clinical management of individuals with ASD and a precision medicine approach.

Full text

EDITED BY
David Coghill,
The University of Melbourne, Australia
REVIEWED BY
Giulia Purpura,
University of Milano Bicocca, Italy
Ana Moscoso,
Hôpital Robert Debré, France
*CORRESPONDENCE
Federica Donno
federica.donno87@gmail.com
†
Deceased
SPECIALTY SECTION
This article was submitted to Autism and Other
Neurodevelopmental Disorders, a section of
the journal Frontiers in Child and Adolescent
Psychiatry
RECEIVED 21 January 2023
ACCEPTED 15 March 2023
PUBLISHED 21 April 2023
CITATION
Donno F, Balia C, Boi J, Manchia M, Zuddas A
and Carucci S (2023) Social and executive
functioning in individuals with autism spectrum
disorder without intellectual disability: The
case–control study protocol of the CNeSA
study.
Front. Child Adolesc. Psychiatry 2:1149244.
doi: 10.3389/frcha.2023.1149244
COPYRIGHT
© 2023 Donno, Balia, Boi, Manchia, Zuddas and
Carucci. This is an open-access article
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Commons Attribution License (CC BY). The use,
distribution or reproduction in other forums is
permitted, provided the original author(s) and
the copyright owner(s) are credited and that the
original publication in this journal is cited, in
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No use, distribution or reproduction is
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terms.
Social and executive functioning
in individuals with autism
spectrum disorder without
intellectual disability: The
case–control study protocol of
the CNeSA study
Federica Donno1,2*, Carla Balia2, Jessica Boi2, Mirko Manchia3,4,5,
Alessandro Zuddas1,2†and Sara Carucci1,2
1
Section of Neuroscience & Clinical Pharmacology, Department of Biomedical Science, University of
Cagliari, Cagliari, Italy,
2
Child & Adolescent Neuropsychiatric Unit “A. Cao”Paediatric Hospital, ASL Cagliari,
Cagliari, Italy,
3
Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy,
4
Unit of
Psychiatry, Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy,
5
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada
Several studies suggest that children and adolescents with autism spectrum
disorder (ASD) often present deficits in executive functions (EFs). The research
on cold EF shows a high heterogeneity across different cohorts of patients as
well as different study designs, while studies investigating hot EF and their
relationship with different ASD phenotypes are still limited and related only to
specific domains, although this concept could contribute to clarify the
phenotypical variability by explaining the difficulties encountered by individuals
with ASD in daily life, where stimuli are often emotionally charged. With the aim
to identify specific neuropsychological profiles in children and adolescents with
ASD without intellectual disability, we designed a study protocol comparing a
clinical sample of individuals with ASD to aged-matched (10–17 years) typically
developing controls (TDC) on a neuropsychological test battery investigating
both “cold”and “hot”EF with the purpose of further investigating their
relationships with ASD symptoms. Autonomic measures including heart rate,
heart rate variability, skin conductance, and salivary cortisol were also recorded
before/during/after the neuropsychological testing session. This paper describes
the case–control study protocol named “Caratterizzazione NEuropsicologica del
disturbo dello Spettro Autistico, senza Disabilità Intellettiva, CNeSA study,”its
rationale, the specific outcome measures, and their implications for the clinical
management of individuals with ASD and a precision medicine approach.
KEYWORDS
autism spectrum disorder, neuropsychological functioning, autonomic functioning, control
design, social cognition, hot executive functions, cold executive functions, study protocol
Introduction
Autism spectrum disorder (ASD) is a complex, lifelong, and multifactorial
neurodevelopmental condition with onset in the first years of life. The Diagnostic and
Statistical Manual of Mental Disorders, Fifth Edition (DSM 5) (1) introduced the term
“spectrum”to highlight the broad heterogeneity of etiologies, onsets, clinical entities, and
prognostic trajectories. Furthermore, individuals affected by ASD present heterogeneous
TYPE Study Protocol
PUBLISHED 21 April 2023
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DOI 10.3389/frcha.2023.1149244
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neuropsychological profiles, due to the combination of several
genetic and environmental factors that complexify the diagnosis
and tailored interventions (2).
Children and adolescents with ASD without intellectual
disability (ID) can use compensatory strategies for dealing with
their difficulties in social contexts thus improving their social
functioning (3,4). However, they maintain significant difficulties
in grasping social cues and other intentions, and have limited
intuitive judgment skills and more inflexible decision-making
processes (5,6) as well as a lower sensitivity to rewards rather
than punishments (7). Furthermore, individuals with ASD
without ID may present atypical emotional responses to a
stimulus and high aversive motivation toward social stimuli (8)
with consequent impairment in their social functioning during
daily life. Even when they present correct moral judgment,
individuals with ASD tend to estimate certain transgressions or
unfair acts more seriously than those with typical development,
showing they rely on more rigid moral criteria (9).
Several theories tried to explain the core of social functioning
difficulties in individuals with ASD (10–12). The hypothesis of
executive disfunction (13,14) includes deficits in the following
functions: attention; flexibility and set-shifting; planning;
inhibitory control; generativity; and working memory (15). Early
studies reported a relationship between set-shifting impairment
and restricted and repetitive behaviors (16,17) and difficulties in
facing changing situations (14). Disorders in selective attention
were associated with restricted and repetitive behaviors (18,19)
while deficits on working memory were associated with
difficulties in social communication and interaction, as the ability
to take others perspective, social reciprocity and initiation (20).
Moreover, a lack of generativity could compromise the quality of
communication, due to the difficulty in generating ideas relevant
to the context of conversation with others (21). Despite these
results, the research on executive dysfunction in ASD shows
contrasting results for the high variability in study designs and
cohorts of patients (22,23).
Furthermore, an early impairment in multisensory and
sensory–motor integration (24,25) is widely observed in children
with ASD.
In children with ASD, the severity of sensory symptoms and
intelligence quotient (IQ) seem to predict motor abilities,
suggesting a relationship between the sensory, motor, and
cognitive domains (26). A severe complex sensory processing
impairment also appears to impact their motor variability (27).
In a seminal study, children with ASD aged younger than
4 years performed fewer exploratory actions on objects within
a naturalistic setting, or engaged in repetitive, primitive
sensorimotor actions compared to their typically developing (TD)
peers who instead were more prone to explore action possibilities
during means-end tasks (28). Difficulties in both fine and gross
motor abilities can limit infants’active exploration of objects and
their ability to discover means-end relationships (29,30).
The sensorimotor difficulties are often associated with
behavioral motor problems, such as stereotyped behavior and
restricted interests. Other studies found the presence of a
relationship between early motor delay and later communication
delay in infants at risk for ASD (31,32), with a cascading effect
on all aspects of neurodevelopment, including detail perception,
motor planning, social communication, and cognitive domains.
In the last decade, a distinction between “cool”and “hot”
executive functions (EFs) (33) has been introduced with the aim
to discriminate the purely cognitive processes from those elicited
by affective stimuli or related to emotionally salient situations in
which emotional and cognitive processes are integrated to
generate a behavior (34,35). The “hot”EFs could contribute to
explain the difficulties encountered by individuals with ASD in
daily life where stimuli are often charged emotionally.
The high difficulty in managing daily changes, unpleasant
events, negative social interactions, and external sensory stimuli
also leads individuals with ASD to experience greater stress than
neurotypical individuals (36).
Several studies suggest that heart rate (HR), heart rate
variability (HRV), electrodermal activity (EDA), and cortisol
levels appear to be altered in the ASD population: children with
ASD seem to present a chronic state of hyperarousal (37–39), a
psychophysiological inflexibility to stimuli (e.g., appropriate vagal
withdrawal to attention-demanding stimuli) (40), and greater
physiological responses to threat (41). Although individuals with
ASD present a greater lower overall regulation than their
typically developing peers, the ASD patients without intellectual
impairment demonstrate more autonomic flexibility and
responsiveness to stimuli (42) than those with intellectually
impaired ASD (39). Moreover, ASD in individuals without
intellectual impairment exhibits more autonomic responsivity
showing more variable cardiac responding to familiar vs
unfamiliar social situations in comparison to TD controls
(TDCs) who do not show changes across stimuli (42).
Other studies investigating stress levels by measuring the
salivary cortisol also report higher cortisol levels in individuals
with ASD compared to both younger autistic individuals and
age-compared TDCs during social interactions with peers (43,44).
Numerous studies report the presence of a relationship between
autonomic nervous system (ANS) activity and social and
communication functioning in individuals with ASD (45–48).
Relative to TDCs, patients with ASD present greater
electrodermal activity during feedback rewards and the greatest
increases were more likely exhibited by children with more
repetitive symptoms, reduced executive functions, and
internalizing symptoms (46).
According to these notions, some studies support the
hypothesis that stress, either acute or chronic, affects cognitive
performances and the way in which individuals with ASD
perceive, understand, and react to the social world (49,50).
Excessive levels of stress have been associated with poorer
performance in short-term memory tasks, learning, and attention
tasks (51,52). It is not yet clear, however, whether the cognitive
dysfunctions observed in individuals with ASD entails a greater
susceptibility to stressful situations or, conversely, whether stress
produces an influence on the performance of cognitive tasks.
Moreover, to date, the studies investigating both hot and cold
EFs are still limited, and the research is often focused on singular
domains.
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Considering the current literature, further research is required
to understand the neuropsychological characteristics of patients
with ASD in both domains of hot and cold EFs and how they
differ from TDCs. Exploring the relation between symptom
phenotypes, neuropsychological functioning and autonomic
nervous system response will enhance the current knowledge on
the neurobiological mechanisms underlying the difficulties
presented by individuals with ASD. This may allow the
identification of cognitive and physiological pathways underlying
the disorders and improve the intervention strategies to support
patients’autonomy in daily life activities.
Furthermore, the assessment of physiological parameters in
association with the behavioral performance could help the
clinician to understand the way the individuals with ASD process
the experiences related to hot and cold tasks.
With this purpose in mind, we designed the present protocol to
compare a clinical sample of individuals with ASD to aged-
matched TDCs to investigate their neuropsychological
functioning and the relationships with ASD symptoms.
Methods and analysis
Study design
This is a monocentric study including two phases: a screening
and clinical assessment visit (phase I); and a case–control study
(phase II) comparing the neuropsychological and autonomic
functioning profiles of children and adolescents with ASD
without ID to age-matched TDCs.
Participants
Two cohorts of children and adolescents (aged 10–17 years and
10 months at screening visit) of both genders were enrolled in the
study.
Group 1 (ASD group) included children and adolescents with a
clinical diagnosis of ASD according to DSM 5 criteria without
intellectual disability (IQ score ≥80).
Group 2 (TDC group) included typically developing children
and adolescents without any psychopathology, matched to the
ASD group for age, gender, and IQ.
Eligibility criteria
Inclusion criteria for all participants
For eligibility, participants from both groups had to be aged
10–17 years and 10 months at the screening visit with an IQ >80
measured with Wechsler IQ scales (Wechsler Intelligence Scale
for Children—Fourth Edition, WISC-IV or Wechsler Adult
Intelligence Scale-IV, WAIS-IV) administered within 2 years
before enrollment into the study.
ASD group inclusion criteria
Participants in the ASD group had to comply with the
following requirements:
•Diagnosis of ASD in accordance with the DSM 5 criteria
formulated by a qualified clinician according to normal
clinical practice;
•Drug-naïve for psychotropic medications or off any
psychotropic medication [psychostimulants, antipsychotics,
serotonin and norepinephrine reuptake inhibitors (SNRIs),
mood stabilizers, or antidepressants] within the last 6 months
before the screening visit;
•Signed informed consent and absent documents provided by the
individual’s parent/legal guardians and the patients;
•Participants meeting the criteria for co-morbid Attention Deficit
and Hyperactivity Disorders (ADHD), Anxiety, or Post
Traumatic Stress Disorder (PTSD) as well as language and
motor disorders were not excluded from the study (as for the
clinical judgment of the investigator).
TDC group inclusion criteria
The participants included in the TDC group had to comply
with the following requirements:
•A total score on the Social Communication Questionnaire
(SCQ) below the clinical range for ASD: ≤10;
•Drug-naïve for psychotropic medications;
•Signed informed consent and absent documents provided by the
individual’s parent/legal guardians and the TDCs.
Exclusion criteria ASD group
Potential eligible participants for the ASD group were excluded
from participation in the study if they met the following criteria:
•IQ <80 (Wechsler IQ scales, within the last 2 years before
enrollment);
•Presence of a primary DSM 5 diagnosis of schizophrenia-related
disorders, schizophrenia, bipolar disorder, depression;
•Presence of any acute or unstable medical condition
compromising the reliability of the study;
•The participant had any psychotropic medication (psychostimulants,
antipsychotics, SNRIs, mood stabilizers, or antidepressants) within
the last 6 months before the beginning of the study;
•Biological siblings of the participants were already included
within the ASD group.
Exclusion criteria TDC group
Potential TDCs were not enrolled into the study if they met any
of the following criteria:
•IQ <80 (Wechsler IQ scales, within the last 2 years before
enrollment);
•The participant was treated with any psychotropic medication
(psychostimulants, antipsychotics, SNRIs, mood stabilizers, or
antidepressants);
•The presence of a primary DSM 5 diagnosis of ADHD,
oppositional defiant disorder (ODD), conduct disorder (CD),
or any other psychiatric condition;
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•The presence of any acute or unstable medical condition
compromising the reliability of the study.
Sample size calculation
To compare the performance between the ASD and TDC
groups, a sample size of 40 ASD cases and 40 TDCs had a
statistical power of >80% at the 0.05 level to detect group
differences with a moderate effect size allowing for the inclusion
of covariates (sex, site, children vs adolescents, IQ, co-morbidity
with ADHD) (53).
Enrollment
The ASD group was composed of inpatients or outpatients or
clinical referrals from community centers and their parents were
informed about the study by the clinical team or the study
investigators. TDCs were identified through other clinical
departments or from ASD participants’family members or
classmates who wanted to participate in the study.
Before starting any procedures, the parents/legal guardian and
the child/adolescent provided written informed consent and the
assent for participating in the study.
All participants were free to withdraw from the study at any
time, for any reason, and without any consequences to their
clinical treatment. The investigator could decide to withdraw an
individual from the study for urgent medical or psychiatric
reasons and a new participant was recruited from the same
group (ASD/TDC) and gender as the individual who withdrew
from the study. Data collected until the point of withdrawal were
collected and included in the final analysis.
Study procedures
This study is a non-interventional case–control study
divided into two phases: the screening and clinical assessment
visit (phase I); and the case–control study including
neuropsychological testing and physiological measures collection
(phase II). To reduce the fatigue effect on testing performance,
the case–control phase was divided into 2 days (visits 0a and 0b)
(Figure 1; see also Supplementary Material Table S1: study design).
Screening and clinical assessment visit (phase I)
After receiving the signed informed consent and assent,
sociodemographic information and data on medical, psychiatric,
and pharmacological history of participants as well as medical
history of relatives were collected for all participants and all
criteria for enrollment were verified.
The screening session included the following (see
Supplementary Material Table S2: clinical assessment; SM1:
Description of screening and clinical instruments):
•WISC-IV (54) or WAIS-IV (55);
•Kiddie Schedule for Affective Disorders and Schizophrenia—
Present and Lifetime Version (Kiddie-Sads-PL) (56).
An evaluation of autistic symptoms was different among the two
groups.
Children/adolescents with ASD underwent a detailed
psychiatric assessment for autistic symptoms using the following
principal instruments for the diagnosis of ASD:
•Autism Diagnostic Interview—Revised (ADI-R) (57);
•Autism Observational Scale—Second Edition (ADOS-2) (58).
FIGURE 1
Study design. *The intellectual level is measured using Weschler scales (WISC-IV or WAIS-IV); behavioral problems are assessed with Kiddie-SADS-PL,
CPRS-RS, NCBRF-TIQ, MOAS, ICU, C-GAS, and CGI; the assessment of autistic symptoms includes ADOS-2, SCQ, SRS-2, and EQ-40; internalizing/
externalizing symptoms are evaluated with CBCL, TRF, and YSR; the assessment of executive functions includes the BRIEF questionnaire.
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Parents of the participants included in TDC group completed the
SCQ (59). A score of 10 is used as the cutoff for excluding
autism in the participant.
Further assessments included the following:
•Modified Overt Aggression Scale (MOAS) (60);
•The Nisonger Child Behaviour Rating Form (NCBR-TIQ)
parent version (61);
•Clinical Global Impression-Severity (CGI-S) (62);
•Children’s Global Assessment Scales (C-GAS) (63).
Participant forms:
•Self Report (YSR) (64);
Parent and teacher forms:
•Social Responsiveness Scale—Second Edition (SRS-2) (65);
•Child Behavior Checklist (CBCL), Teacher Report Form (TRF)
(64);
•Conner’s Parent Rating Scale-Revised (CPRS-RS) (66);
•Behavior Rating Inventory of Executive Function (BRIEF) (67);
•Empathy Quotient (EQ-40) (68);
•Inventory of Callous Unemotional Traits (ICU) (69).
Vital signs, body temperature, height, and weight
Vital signs (blood pressure, heart rate), body temperature,
height, and weight were recorded; a physical examination was
also performed.
Case–control study (phase II)
Within 1 month from the screening visit, each participant took
part in the case–control study consisting of neuropsychological
testing (Figure 1). The computerized test battery was split into
three sessions lasting 3 hours in total to perform over 2 days
(visits 0a and 0b) at a maximum interval of 1 week.
In the first of the 2 days (visit 0a), the first session of
neuropsychological tests comprising five tasks was administered
lasting approximately 50 min in total (Table 1); during the
second day (visit 0b), the participants completed the second and
third sessions, each consisting of four tasks (Table 2). The
second and third sessions were separated by an interval of
45 min during which the participant rested.
During all three sessions, the autonomic parameters HR, HRV,
and EDA were collected through the application of the E4
wristband worn by the participant 20 minutes before the start
until the end of the session.
During visit 0b, two samples of saliva were collected from all
participants: 5 min before the first testing session and
immediately after the end of the second session, in order to
detect salivary cortisol levels.
The neuropsychological test battery
In this study, a computerized battery of neuropsychological
tasks was used with the aim of exploring both the “cold”
and “hot”EFs. All tasks were administered using a touchscreen
tablet (10.1-inch screen) and included tasks from the
neuropsychological test batteries “Cambridge Neuropsychological
Automated Battery”(CANTAB; Cambridge Cognition: RRID:
SCR_003001 https://www.cambridgecognition.com/cantab/) (70)
and the EMOTICOM battery (71).
Three different domains of cold EFs (the sustained attention,
the acquisition and maintenance of rules, and the set-shifting
abilities and the visual working memory) were evaluated using
three tasks from the CANTAB battery.
The tasks chosen to evaluate the domains of hot EFs
(emotional processing, motivation and reward, impulsivity and
social cognition, social decision-making) were derived by the
EMOTICOM battery. For a detailed description of the
administered neuropsychological tasks, see Supplementary
Material: SM2: Neuropsychological Assessment.
A screening test was first administered with the aim of making
the individual familiar with the tablet and other test materials.
Within each visit, the presentation order of the tests was
randomized for each participant.
Physiological measures
The stress levels due to task administration were evaluated
through physiological measures collection (Table 3).
TABLE 1 First neuropsychological assessment session (visit 0a).
Neuropsychological tasks Functions Category
Intra/extra-dimensional set-
shifting (IED)
Attentional set formation
maintenance, shifting, and
flexibility
Cold executive
functions
Face and Eyes Emotion
Recognition Task (FEERT)
Emotion recognition Emotional
processing
Delay Discounting (DD) Impulsivity, rate of discount
across delays, and
probabilities
Impulsivity
Moral Judgment (MJ) Moral emotions Social
cognition
Prisoner Dilemma (PD) Social decision-making,
cooperation
Social
cognition
TABLE 2 Second neuropsychological assessment session (visit 0b).
Neuropsychological
tasks
Functions Category
Rapid Visual Processing (RVP) Sustained attention Cold executive
functions
Delay Matching to Sample
(DMS)
Visual matching and short-
term visual recognition
memory
Cold executive
functions
Progressive Ratio Task (PRT) Incentive motivation,
motivational “breakpoint”
Motivation and
reward
New Cambridge Gambling
Task (NCGT)
Value-based decision-making,
reward and punishment
sensitivity, risk-taking behavior
Motivation and
reward
Face Affective Go No Go Task
(FAGNG)
Attentional affective bias Emotional
processing
Reinforcement Learning Task
(RLT)
Learning based on reward and
punishment
Motivation and
reward
Ultimatum Game (UG) Social decision-making,
sensitivity to fairness and
tendency to inflict punishment
Social
cognition
Theory of Mind (ToM) Social ToM information
preference in ambiguous scenes
Social
cognition
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Autonomic measures using Empatica E4.
During the neuropsychological assessment, task-related stress
and arousal levels were assessed with the application of the
Empatica E4 wristband recording the autonomic measures HR
and HRV by a photoplethysmography technique, and EDA. The
bracelet was placed on the wrist of the non-dominant hand of
the participant. The recording started at least 5 min before the
testing session, while the participant was at rest, to yield baseline,
and continued during the performance of the whole
neuropsychological test battery.
During the test administration, a “tag event”function was used
to delimit the beginning and the end of each test with the purpose
of comparing stress and arousal levels during different
neuropsychological tasks. The tag event delimiting the end of the
task does not correspond with the start of the next task. Data
collected during the period between the end of a task and the
beginning of the next were excluded from the analysis.
Collection of saliva cortisol samples
During the second day of neuropsychological testing (visit 0b),
two samples of saliva were collected with a “passive drool”method.
Each 0b visit was scheduled in the morning to collect a baseline
sample in a time window between 8:00 and 9:30, 5 min before
the start of the first testing session. The stress sample was
collected at the end of the second session, depending on the time
needed for the execution of all tasks. The time of both
collections was reported in the patient’s case report form (CRF)
to consider the circadian trend of cortisol by age.
If the participant had trouble spitting, sugar- and flavor-free
chewing gum were provided to assist salivation. They were asked
to rinse their mouth with water and then waited approximately
1 minute before saliva collection.
All samples were centrifuged after collection and then frozen
and stored at −20°C until assay. Cortisol levels were extracted by
an external lab (San Raffaele Hospital, Milano, Italy).
A difference between salivary cortisol levels at baseline and at
the end of administration was calculated, within and between the
two groups.
Outcome measures
Primary outcome measures included the following: quantitative
and qualitative behavioral measures evaluated through the
neuropsychological test battery: measures of cold (sustained
attention, attentional set formation maintenance, shifting, visual
matching, and short-term visual recognition memory) and hot
EFs (emotion recognition, attentional biased, reward-punishment
sensitivity, moral judgment, cooperation, theory of mind, test
completion, motivation). These were calculated using the following:
•response latency (reaction times);
•accuracy (number or proportion of errors).
The following physiological measures were recorded: heart rate;
heart rate variability; skin conductance at rest and during the test
performance; and salivary cortisol levels before and after testing
session.
The secondary outcome measures were as follows: clinical
measures to assess the association between autistic symptoms
severity; co-morbidities; problem behaviors obtained by the
administration of tests, interviews, rating scales, and
questionnaires; and neuropsychological profile. These were
obtained using the following:
•Screening questionnaires: SRS-2, CBCL, TRF, YSR, CPRS,
BRIEF, ICU;
•Screening rating scales: MOAS and Nisonger;
•CGI-S, C-GAS.
Handling and storage of data and
documents
Data were handled confidentially and anonymously: a different
participant identification code was used to link the data to each
individual. The key to the code was safeguarded by the
investigators. Demographic data (name, address, etc.) and
identification numbers were coupled in a file, which was saved
on a password-protected PC, only accessible to the investigators.
The handling of personal data complied with Personal Data
Protection Acts.
A unique code was given to each collected salivary sample,
consisting of the type of sample, the visit session and the date of
collection, and a unique, consecutive number. The code was not
based on the patients’initials and birthdate.
Statistical analysis
The cognitive-behavioral measures for each task include mean
reaction time, number or proportion of errors, and other
quantitative measures.
The group differences will be evaluated using chi-square or
one-way analysis of variance (ANOVA) tests in case of the data
meeting the assumptions of normality and homogeneity of
variance, while the effect of covariates will be explored using
analysis of covariance (ANCOVA) and, thereafter, by
determination of simple effects or interactions. Non-parametric
tests (e.g., Mann–Whitney Utest) or bootstrap-based non-
parametric ANOVA will be used for variables that do not respect
these assumptions. Simple and multiple and logistic regression
models will be applied to the whole sample and to the ASD
group. A mixed repeated-measures analysis will be used to
compare the performance of ASD to the TD group within each
task when appropriate.
TABLE 3 Autonomic measures and instruments.
Category Tools Measures of stress response
Autonomic Measures E4 wristband Heart rate (HR)
Heart rate variability (HRV)
Skin conductance (EDA)
Salivary sampling Salivary cortisol (pre and post)
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Variables including age, gender, IQ, and co-morbidities such as
ADHD, anxiety, and depression, will be also investigated as
covariates.
Correlations, simple and multiple regressions, and ANCOVAs
will be used to investigate the demographic, clinical,
neuropsychological, and neurophysiological predictors to
establish their role as moderating or modulating variables with
symptom severity.
If, as expected, the raw cortisol values are positively skewed,
they will be normalized using log transformation. To assess the
group differences in cortisol variations, mixed repeated-measures
ANOVAs will be performed with the group variable as a
between-subjects factor and time (pre- and post-testing) as a
within-subjects factor; the collection time of the samples will be
used as a covariate.
One-way ANOVAs will be used for group comparisons of HR,
HRV, and skin conductance means during the task performance.
To quantify HR, HRV, and skin conductance responsiveness to
the stress related to the performance during tasks, the change
relative to baseline will be calculated. A clustering analysis will be
also used to group individuals belonging to the whole sample in
classes not defined a priori, according to autonomic characteristics.
Discussion and clinical implications
ASD is a condition characterized by impaired socioemotional
skills and patterns of restricted and repetitive interests and
behaviors lasting in general for a lifetime. Although patients with
ASD without ID implement compensatory strategies to face
difficulties, most of them experience negative experiences, such as
social isolation, and have few opportunities for sociability (72,
73). When they make friends like their TD peers, compared to
the latter they experience a poorer quality of friendship (74). The
presence in ASD individuals of hyper moral behaviors, such as
scolding classmates who break the school rules or trying to
socialize with peers or monopolizing speeches, make individuals
with ASD vulnerable to bullying episodes. Furthermore, their
difficulties in recognizing social cues [e.g., difficulties
understanding the communicative intent of gaze (75,76)], the
tendency to incorrectly interpret others’behavior (77,78) as well
as difficulties in interpreting verbal communication (79,80)
compromise the identification of bullying episodes, leading them
to experience uncomfortable emotions.
To date, published studies on the neuropsychological
functioning of ASD show contrasting results due to methods
issued without providing exhaustive answers in explaining the
neuropsychological dysfunctions in the ASD population. Studies
on social decision-making as cooperation indicated lower correct
predictions of others’moves compared with TDCs (81) and an
improvement of this ability with age (82,83). Moreover, for
individuals with ASD, their cooperation relies on more rigid
criteria that does not differ depending on the morality of the
interacting partner (84). In contrast, other studies report similar
cooperation behavior in autistic and non-autistic individuals (85).
Autistic individuals appear to make less use of contextual cues
and reported less emotion reaction to the scenarios described in
vignettes (86,87).
In addition, the studies on reward-based decision-making
using the gambling task reported contrasting results. Whereas the
study by Faja et al. (46) showed a similar pattern of gambling
selection between individuals with ASD and TDCs, the study by
Yechiam et al. showed that, unlike TDCs, individuals with ASD
presented fewer advantageous choices and difficulties in
developing and maintaining a congruent choice strategy
switching from a deck to another (88).
Considering the lack of knowledge in the field and the high
heterogeneity of the ASD, the present study will help to better
define the neuropsychological and autonomic characteristics
underpinning ASD in order to provide useful information to
identify the underlying potential neuropsychological/physiological
mechanisms behind the clinical symptoms. Although several
therapeutic strategies have already been developed to help autistic
patients in dealing with social and emotional difficulties,
including video modeling (89,90), emotional recognition training
(91,92), social stories (93), and social skill training (94,95), our
study could contribute to develop further targeted intervention
strategies.
Targeted interventions should consider the importance of
factors that typically contribute to the valuable perception of
social situations, including emotions and motivation, the stimuli
relevance, the reward and punishment sensibility, the attentional
affective bias vs. stimuli, and the uncertainty valence. For
example, individuals with autism can orient their attention
toward a stimulus rather than another leading to dysfunctional
decision-making thus compromising their social functioning and
their autonomy development. The results of this study will help
to provide the basis for developing more effective psycho-
educational strategies aimed at improving patients’autonomy
and at enhancing their social skills.
Strengths and limitations of this study
The main strength of the present study protocol is to
investigate, at the same time, both domains of hot and cold EFs
as well as the autonomic functioning in a cohort of individuals
with autism.
Another strength of this study is the wide neuropsychological
and clinical characterization of the ASD sample within a narrow
age range including different sources of information (parents,
teachers, and the individuals themselves).
On the other hand, the co-morbidity with other
neurodevelopmental disorders, such as ADHD or specific
learning disorders, could represent a limitation of the study due
to their influence on the task performances (e.g., tasks requiring
reading words could be less suitable for patients with dyslexia,
therefore requiring additional efforts; the length of tasks could
Donno et al. 10.3389/frcha.2023.1149244
Frontiers in Child and Adolescent Psychiatry 07 frontiersin.org

influence the performance in children with hyperactivity or
inattention symptoms). Moreover, the main limitation of this
study is that the Emoticom tasks are not yet standardized in the
pediatric population and the battery administered in this study is
an “experimental”version.
Ethics and dissemination
The present study was approved from the local Ethical
Commitee (Comitato Etico Indipendente) of Cagliari University
Hospital on 28 March 2018 and conducted in accordance with
the principles of the Declaration of Helsinki. Before starting any
study procedure, all participants’parents/legal guardians,
patients, and controls signed an informed consent and assent
document, respectively, as provided for by the national law. The
results of the study will be disseminated through peer-reviewed
publications and at scientific conferences.
Conclusions
An integrative model of neuropsychological functioning in
ASD would better explain the difficulties with ASD. An
understanding of neuropsychological and autonomic functioning
and the relation with ASD symptoms may lead to defining more
effective intervention behavioral strategies that represent first-line
therapy due to the poor responsivity to pharmacological
treatments.
The assessment, which integrates both domains of cold and hot
EFs, can provide insights into the executive deficits that hinder the
development of the skills necessary in ecological social contexts.
Ethics statement
The studies involving human participants were reviewed and
approved by the Local Ethical Committee, Cagliari University
Hospital. Written informed consent to participate in this study
was provided by the participants’legal guardians/next of kin.
Author contributions
FD, CB, and AZ designed the study protocol. FD wrote the
manuscript. FD, CB, MM, and SC worked on the editing, added
minor corrections, and supervised the writing. FD, CB, and JB
contributed to the project administration. FD, CB, SC, and MM
contributed to the revision of the manuscript. All authors have
read and agreed to the published version of the manuscript. AZ
prematurely passed away before the completion of the
manuscript. All authors contributed to the article and approved
the submitted version.
Acknowledgments
The authors thank Trevor W. Robbins, Barbara J. Sahakian,
Rebecca Elliott, and Amy Blend for developing and sharing the
EMOTICOM neuropsychological test battery. The authors are
also grateful to Caterina Medda, who was involved in the project
management, and all the MDs who contributed to the
recruitment phase and organization processes of the study. The
authors also thank the parents/caregivers and their children who
generously dedicated their time to participate in the study.
Finally, the authors wish to express their profound gratitude
toward Professor Alessandro Zuddas, without whom the CNeSA
study would not have been carried out.
Conflict of interest
FD had collaborations as sub-investigator in clinical trials
sponsored by Lundbeck and as an independent rater in clinical
trials sponsored by Servier and Acadia. CB had collaborations
within projects from the European Union (7th Framework
Program) and as a sub-investigator in sponsored clinical trials by
Lundbeck, Otsuka, Janssen Cilag, Angelini, and Acadia. JB had
collaborations as a sub-investigator in sponsored clinical trials by
Angelini and Servier. MM received honoraria from/has been a
consultant for Angelini and Lundbeck. AZ served in an advisory
or consultancy role for Angelini, EduPharma, Servier, Taked, and
Acadia. He received conference support or speaker’s fees from
Angelini and Janssen. He was involved in clinical trials
conducted by Angelini, Janssen, Lundbeck, Otsuka, Roche,
Sevier, and Shire. He received royalties from Giunti OS and
Oxford University Press. SC had collaborations within projects
from the European Union (7th Framework Program) and as a
sub-investigator in sponsored clinical trials by Lundbeck, Otsuka,
Janssen Cilag, Angelini, and Acadia.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed
or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found
online at: https://www.frontiersin.org/articles/10.3389/frcha.2023.
1149244/full#supplementary-material.
Donno et al. 10.3389/frcha.2023.1149244
Frontiers in Child and Adolescent Psychiatry 08 frontiersin.org

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