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Citation: Conte, G.; Costanza, C.;
Novelli, M.; Scarselli, V.; Arigliani, E.;
Valente, F.; Baglioni, V.; Terrinoni, A.;
Chiarotti, F.; Cardona, F.
Comorbidities and Disease Duration
in Tourette Syndrome: Impact on
Cognition and Quality of Life of
Children. Children 2024,11, 226.
https://doi.org/10.3390/
children11020226
Academic Editor: Mark Dzietko
Received: 12 January 2024
Revised: 1 February 2024
Accepted: 4 February 2024
Published: 9 February 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
children
Article
Comorbidities and Disease Duration in Tourette Syndrome:
Impact on Cognition and Quality of Life of Children
Giulia Conte 1, Carola Costanza 2, Maria Novelli 1, Veronica Scarselli 1, Elena Arigliani 1,
Francesca Valente 1, Valentina Baglioni 1, Arianna Terrinoni 1, Flavia Chiarotti 3and Francesco Cardona 1,*
1Child and Adolescent Neuropsychiatry Unit, Department of Human Neuroscience, Sapienza University
of Rome, 00185 Rome, Italy; giulia.conte@uniroma1.it (G.C.); maria.novelli@uniroma1.it (M.N.);
veronicascarselli@gmail.com (V.S.); ele.arigliani@gmail.com (E.A.); francescavalente87@gmail.com (F.V.);
valentina.baglioni@uniroma1.it (V.B.); a.terrinoni@policlinicoumberto1.it (A.T.)
2Department of Sciences for Health Promotion and Mother and Child Care “G. D’Alessandro”,
University of Palermo, 90128 Palermo, Italy; carola.costanza@unipa.it
3Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy;
flavia.chiarotti@iss.it
*Correspondence: francesco.cardona@uniroma1.it
Abstract: Background: Cognitive functions represent foundational factors for mental health and
quality of life (QoL). In Tourette syndrome (TS), psychiatric comorbidities are common and have
been inconsistently reported to affect the cognition and QoL of patients, while the role of tic disorder
duration has not been yet explored. Methods: To examine how comorbidities and TS duration may
influence cognition and QoL, N= 80 children with TS (6–16 years) were evaluated using the Wechsler
Intelligence Scale for Children (WISC-IV). Standardized questionnaires were used to assess the pres-
ence and severity of TS main comorbidities and QoL. Data were interpreted using linear correlations,
regression, and mediation analysis. Results: Depression and attention-deficit/hyperactivity disorder
(ADHD) symptoms accounted for poorer cognitive performance. Anxiety oppositely predicted
better cognitive performance, while no significant role for obsessive compulsive disorder (OCD)
was observed. Disease duration was associated with lower total IQ, verbal reasoning, and working
memory abilities. Depression, anxiety, and TS duration also deeply influenced QoL measures. Con-
clusions: TS common comorbidities have a differential impact on the cognitive abilities of children
and adolescents, which translates into a complex influence on their perceived QoL. A longer clinical
history of tics was related to worse cognitive outcomes, which prompts further consideration of
disease duration in both clinical and research settings involving children and adolescents.
Keywords: Tourette syndrome; comorbidities; disease duration; cognition; cognitive profile; quality
of life; obsessive compulsive disorder (OCD); attention-deficit/hyperactivity disorder (ADHD);
depression; emotional dysregulation
1. Introduction
Tourette syndrome (TS) is a complex childhood-onset neuropsychiatric condition char-
acterized by motor and vocal tics—i.e., repetitive, sudden, involuntary movements or
vocalizations—which occur for at least one year [
1
]. Although the majority of people living
with mild forms of TS lead satisfying lives, those with greater tic severity and persistent
symptoms may experience a significant negative impact on their overall quality of life and
well-being [2].
There is extreme variability in the clinical presentation of TS [
3
,
4
] and in the associated
clinical conditions, i.e., comorbidities, that are usually developed by two-thirds of affected in-
dividuals and often arise during childhood or early adolescence [
5
–
7
]. Comorbidities include
several neurodevelopmental and psychiatric disorders such as attention-deficit/hyperactivity
Children 2024,11, 226. https://doi.org/10.3390/children11020226 https://www.mdpi.com/journal/children
Children 2024,11, 226 2 of 18
disorder (ADHD) [
6
], obsessive compulsive disorder (OCD) and other repetitive behav-
iors [8,9], depression [10,11], and anger dysregulation with disruptive behaviors [12].
Coupled with disabling and long-lasting tics, comorbidities can all lead to poorer
psychosocial functioning and quality of life (QoL) [
13
,
14
]. Comorbid disorders have been
linked to greater TS severity [
3
] and a greater load of socially inappropriate behaviors which
fall within the spectrum of complex tics (such as copropraxia or coprolalia), potentially
leading to poor psychosocial adjustment [
15
]. Comorbid disorders are also associated
with greater TS duration [
4
] and a greater impact on health-related QoL [
14
,
16
]. However,
the effect of comorbidities on QoL extends beyond their association to more severe tic
phenotypes. Depression, anxiety, OCD, and ADHD not only act on well-being through
the psychopathological mechanisms inherent to each one of them (e.g., low self-esteem in
anxiety and depression, poor frustration tolerance and impulsivity in ADHD and disruptive
behaviors, leading to social isolation and exclusion or poor academic progress), but are also
significantly burdened by variable but enduring impairments in cognition, and specifically
in attention, memory, and executive functions [17–22].
Cognitive functions, by enabling individuals to categorize and remember information;
maintain attention for reasoning; adapt responses to changes in the environment, personal
goals, etc.; represent foundational factors to learn and attain education [
23
,
24
]; reach a success-
ful transition to adulthood [
25
]; and, most importantly, maintain good mental health [
26
,
27
].
While intelligence is generally considered to fall within the average range in TS [
28
], several
studies point to minor neuropsychological deficits regarding inhibition, cognitive flexibility,
and working memory [
29
–
31
], while others conversely support the presence of enhanced
cognitive abilities with respect to procedural learning [
32
] and inhibitory control [
33
,
34
].
Thus, no conclusive evidence is available to date regarding cognition in TS and how this
is affected by the different combination of TS’s typical comorbidities. Nonetheless, investi-
gating cognition in neuropsychiatric disorders appears relevant for patients in all levels of
care. Interestingly, in depressive and psychotic spectrum disorders, cognitive functioning
is a predictor of the illness course in the long-term, independently from the variation of
symptoms defining the clinical picture (e.g., hallucinations in schizophrenia, mood regulatory
problems in depression) [
35
,
36
]. Moreover, cognition is not only increasingly recognized as
a key determinant for well-being throughout developmental ages and later in life [
37
,
38
]
but may also represent a promising target for novel treatments aimed at training cognitive
functioning with the ultimate goal of improving functional outcomes and QoL—the so-called
cognitive remediation strategies
[39–42]
. Regarding comorbidities, while ADHD has been
extensively reported to negatively influence cognition in the specific context of TS [
43
–
48
],
data on how OCD, anxiety, and depression may impact the cognitive functioning of people
with chronic tics are much scarcer, at best. Additionally, evidence on the extent to which
each different comorbidity moderates cognitive performance in TS remains hampered by
the categorial approaches implemented by prior studies, which parse the clinical spectrum
into classes or groups (e.g., TS + ADHD vs. TS + OCD vs.
TS + ADHD
+ OCD, etc.). These
have the downside of creating simplistic differentiations of the clinical picture of TS, possibly
lacking ecologic validity for a nuanced spectrum in which comorbidities combine differently
from one patient to another, both in terms of type and severity.
Not only do comorbidities have enormous interindividual variation in TS, but tics also
do. Tics may also dramatically change during the life course of TS for the single affected
person, both in severity and persistence over time. Prior studies showed that a younger age at
tic onset [
44
,
49
] and greater tic severity [
49
,
50
] seem to negatively influence cognitive abilities,
although such effects were not confirmed in larger population-based groups of children [
51
].
As for the persistence of tics over time, little is currently known about how this variable may
influence the QoL of people with TS, and in which way it may do so. Although disease
duration has been scantly considered in the clinical literature around TS, having to deal with
more persistent tics or being under the burden of repeating episodes of tic exacerbations is
highly likely to play a role in the well-being and functioning of people living with TS. Still, it
Children 2024,11, 226 3 of 18
is unknown whether a greater disease duration may harm patients’ QoL by acting on their
cognitive functioning as much as other tic-related factors previously outlined.
Against this background, studies aimed at evaluating if and to what extent the vari-
able clinical severity of TS influences cognition and QoL appear of critical importance
to promote optimal care for all patients, and children particularly. Prior TS studies have
approached this issue, providing mixed results, which may have arisen from TS’s typical
heterogeneity. Therefore, the present study aimed to explore how much tic-related clin-
ical aspects, on one side, and comorbid disease load, on the other, impact the cognitive
functioning of children with TS and if this is relevant to their emotional, academic, and
social functioning and overall well-being. More specifically, we implemented a dimensional
approach that accounts for the variability in tic and comorbid disease severity on cognitive
performance and QoL, without parsing the clinical spectrum of TS into rigid categories
(e.g.,
TS + depression
vs. TS + ADHD vs. TS + OCD, and so on) that may fall short of
ecological validity [
4
] and add little to clinical practice. To our knowledge, this is the
first study to address cognitive functioning and QoL in TS by means of a dimensional
approach in order to reveal the independent contribution of each major TS comorbidity and
tic persistence over time (i.e., disease duration). Based on previous evidence, we assume
that lower cognitive performances may be related to poorer school functioning and quality
of life in children with TS. We also hypothesize that ADHD symptom severity may be
strongly associated with multiple deficits in multiple cognitive domains, while we do not
pose any peculiar hypothesis as regards the role of comorbid OCD, anxiety, and depression,
given the heterogeneous or lacking data from the prior literature. Further, along with the
increasing recognition that disease duration is associated with worse clinical outcomes in
conditions proximal to TS, such as OCD [
52
], we speculate that a longer tic duration may
negatively impact cognition and point out that the issue of disease duration may require
further consideration by studies with clinical populations. Lastly, we aimed to unravel if
cognitive functioning mediates the effect of comorbidities on QoL in TS to inform both
diagnostic and treatment strategies for pediatric patients.
2. Materials and Methods
The outpatient clinic for TS and associated disorders at the Sapienza University of
Rome provides evaluation and treatment for children and adolescents with TS and disor-
ders of the impulsive–compulsive spectrum. All children undergo an intake visit consisting
of a comprehensive anamnesis, a neurological examination, and a few clinical assessments,
including the Yale Global Tic Severity Scale (YGTSS) [
53
] and the Child Behavior Check-
list [
54
] to screen behavioral and emotional problems. Fully qualified child and adolescent
neuropsychiatrists with adequate experience in TS then formulate diagnoses according
to the DSM-5 [
1
]. Thereafter, all patients diagnosed with TS are offered a comprehensive
assessment which includes neuropsychological testing and an evaluation of comorbid
conditions to deliver appropriate treatment for each patient- and family-specific need.
2.1. Participants
Eighty children with TS (72 boys and 8 girls) aged 6–16 years were consecutively
recruited between January 2017 and March 2021 at our specialty clinic. All study data were
drawn from a cumulative clinical sample of children seen for the first time at our clinic
for the standard diagnostic protocol in the timeframe considered for the study. Thus, we
did not operate a sample selection based on clinical characteristics to allow for a greater
representativeness of patients routinely followed at our site. The participants’ data were
all anonymized and stored in an offline electronic repository accessible only to the study
researchers. Due to anonymous data collection, informed consent from participants was
not required. This study was approved by the institutional review board of the Sapienza
University of Rome and performed in accordance with the Declaration of Helsinki.
Children 2024,11, 226 4 of 18
2.1.1. Inclusion Criteria
The following criteria were set for inclusion: children aged 6.0 to 16.11 years, meeting
the clinical diagnosis of TS (ICD-10: F95.2) with or without OCD, ADHD, anxiety, unipolar
depressive disorders, rage attacks, or disruptive behavioral problems.
2.1.2. Exclusion Criteria
The exclusion criteria were defined as follows: other psychiatric conditions or de-
velopmental disorders not typically associated with TS (e.g., autism spectrum disorder,
adjustment disorder, bipolar disorder, schizophrenia spectrum disorders); intelligence
quotients (IQ) (Full-Scale) <70 according to the Wechsler scale of intelligence 4th edition
(WISC-IV) [55]; brain malformations; and genetic syndromes.
2.2. Testing Procedure
A week after intake, children who obtained a TS diagnosis, along with their parents,
were asked to attend three testing sessions, 1.5 h in duration each, to perform cognitive
testing and evaluate possible associated conditions and psychopathological symptoms.
The evaluation was conducted simultaneously and separately with the parents and the
child by two clinicians with solid experience in the administration of the selected study
measures (detailed description of all study measures provided in the following paragraph).
A cognitive evaluation was performed using the WISC-IV battery. A K-SADS-PL clinical
interview [
56
], administered to both the parents and the child, was implemented for the
identification of other psychiatric or neurodevelopmental conditions according to the DSM-
5 criteria. The children were administered the YGTSS, the Children’s Yale–Brown Obsessive-
Compulsive Scale (CY-BOCS) [
57
], the Children’s Depression Inventory (CDI) [
58
], and
the Multidimensional Anxiety Scale for Children (MASC) [
59
]. Parents also completed the
Conners Parent Rating Scale—revised (CPRS-R) [
60
] to rate ADHD symptom severity and
were administered the YGTSS and CY-BOCS to gain information on parental perceptions of
tics and OC symptom severity. As measure of quality of life and school functioning, the
PEDsQol 4.0 [61], was implemented as both a self- and parent-report.
2.3. Measures
2.3.1. WISC-IV
The WISC-IV consists of 10 core subtests providing four indexes of cognitive abilities
standardized for sex and age. Global intelligence, as captured by the Full-Scale IQ (FSIQ)
index, remains one of the single best predictors of academic and occupational success [
62
,
63
]
and appears invariant and unbiased across gender, disability, and ethnic groups [
64
,
65
].
The FSIQ derives from the combination of the four indexes of the WISC-IV, reflecting
the individual’s overall cognitive ability. The mean FSIQ standardized score is 100, with
a standard deviation of
±
15 points. Scores within one standard deviation around the
mean are considered to reflect normal cognitive performance. The Verbal Comprehension
Index (VCI) is the one of the scale’s sub-indexes which measures language expression and
comprehension, as well as the ability of verbal reasoning to solve problems. The Perceptual
Reasoning Index (PRI) reflects the ability to understand visual information and perform
logical reasoning. The Working Memory Index (WMI) evaluates short-term memory and
attention and, finally, the Processing Speed Index (PSI) indicates cognitive speed, but also
relates to other cognitive factors, such as attention, as well as fine motor abilities.
2.3.2. YGTSS
The YGTSS is a reliable clinician-rated interview [
66
] that allows for the notation of
tics currently experienced by the patient, based both on clinical observation and child and
parent reports. Clinicians are asked to separately evaluate motor tics and phonic tics in
terms of number, frequency, intensity, complexity, and interference on a 0–5 scale (with
5 indicating maximum severity). The total score is obtained by summing the scores from
each dimension for both motor and phonic tics on a total scale (0–50 max.). Data from
Children 2024,11, 226 5 of 18
a large validation cohort of children with TS [
67
] have revealed the good to very good
discriminant validity of the YGTSS, as well as acceptable internal consistency (
Ω
= 0.58 for
YGTSS total tic score).
2.3.3. CY-BOCS
The children’s version of the Y-BOCS (CY-BOCS) is the most widely used measure
to assess obsessive compulsive symptom severity. It is a semi-structured interview made
up of 10 items rated on a 5-point Likert scale with a total score of 0–40 points. It evaluates
the severity of obsessions and compulsions across five dimensions, frequency, interference,
distress, resistance, and control, during the last week, and a score above 16 is generally con-
sidered indicative of the presence of OCD (16–23 = moderate severity; 24–40 = severe) [
68
].
2.3.4. CPRS-R
The Conners Parent Rating Scale—Revised, short version (CPRS-R), is a proxy report
used to assess ADHD symptom severity as well as behaviors that might be indicative of
disruptive behavior disorders in children and adolescents ages 3 to 17 years. The Italian
version was implemented for this study [
69
], consisting of 27 items on a 4-point Likert scale,
summed to yield 4 subscales: Oppositional Problems, Cognitive Problems/Inattention,
Hyperactivity, and ADHD index. Raw scores are transformed into T scores, and scores > 70
in the Cognitive, Hyperactivity, and ADHD index subscales offer maximal discrimination
between child and adolescent psychiatric outpatients who were and were not diagnosed
with ADHD [70,71].
2.3.5. CDI
Depressive symptoms were evaluated through the Italian version of the Children’s
Depression Inventory (CDI) [
72
], a 27-item self-report scale for children aged 8–17 years.
The 27 items are scored on a 0–2-point Likert scale and investigate depressive symptoms
across five areas (negative mood, interpersonal difficulties, negative self-esteem, ineffec-
tiveness, and anhedonia). Scores above 20 are considered indicative of clinical depression,
while those higher than 13 are considered an “alarm threshold” [
72
], proving efficient
discrimination of children presenting with depressive spectrum disorders from youngsters
without depressive disorders [73].
2.3.6. MASC
The Italian version of the Multidimensional Anxiety Scale for Children (MASC) is
a 39-item self-report scale for children ages 8 to 19 that covers 4 domains of anxiety
symptoms [
74
]: Physical (tense/restless and somatic/autonomic problems), Social (hu-
miliation/rejection, and public performance fears), Harm Avoidance (perfectionism and
anxious coping), and Separation Anxiety. Single items are scored on a 0–3-point Likert
scale, summed to their corresponding domain, and converted into T scores. Scores > 65
indicate significantly elevated levels of anxiety.
2.3.7. K SADS-PL
The K-SADS-PL is a comprehensive interview allowing clinicians to diagnose current
and past episodes of psychopathology and the presence of neurodevelopmental disorders
in children and adolescents according to the DSM-5 criteria [56].
2.3.8. PEDsQoL
The PeDsQoL 4.0 is a modular self-report and parent-report scale assessing health-
related quality of life in children and adolescents ages 2 to 18. It comprises 23 items
covering four domains of the child’s functioning: Physical, Emotional, Social, and School.
A 0–4-point response scale is used across the age group of 8 to 18 years (with 4 indicating
“almost always a problem”), and items are reverse-scored and linearly transformed to a
0 to 100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0), so that higher scores indicate better
Children 2024,11, 226 6 of 18
functioning. Acceptable reliability and validity for both patient self-reports and parent
proxy reports was detected in the Italian validation study of the scale [
75
]. The self- and
proxy-report measures for children aged over 8 years were implemented for this study.
2.4. Statistical Analysis
A descriptive analysis was conducted to characterize the sample. Quantitative vari-
ables were summarized by means and standard deviations (SDs), and categorical data by
absolute frequencies and percentages. Pearson’s correlation analyses were carried out to
verify possible co-variations between quantitative variables. Age; age at tic onset; YGTSS,
CY-BOCS, CDI, MASC, and CPRS subscales; and WISC scores were all considered for
a pairwise correlational analysis. A linear regression model was carried out using the
FSIQ and WISC sub-indexes as dependent variables to evaluate the independent effect on
cognitive performance of single comorbidities and disease duration. The model included,
as independent variables, TS duration (i.e., the difference between age at evaluation and
age at tic onset), age at tic onset, sex, familial history of tic disorders (Yes vs. No), and
YGTSS, CY-BOCS, CPRS, CDI, and MASC scores. The Variance Inflation Factor (VIF) was
computed to assess the presence of multicollinearity between the independent variables
included in the model, which was suggested by VIF values greater than 5. Since a VIF value
greater than 5 was observed for the CPRS ADHD index subscale, this variable was excluded
from the model. R-squared values were computed to measure the percentage of variance
of the dependent variable explained by the model. R-squared values around 0.13 could
be considered as denoting a moderate effect size, while values about 0.26 or higher could
be interpreted as large effect size [
76
]. The regression analysis results are presented as
unstandardized regression coefficients (b), with significance levels and 95% confidence
intervals (CIs), and standardized (beta) regression coefficients. Finally, to verify if cognitive
functioning mediates the effect of the severity of comorbidities and tics on children’s QoL,
mediation analyses were performed by structural equation modeling (maximum likelihood
estimation method) using the Baron and Kenny approach to test mediation [
77
], including
the FSIQ as a mediator; TS duration and YGTSS, CY-BOCS, CPRS, CDI, and MASC scores
as independent variables; and the PEDsQoL Total, Physical, Emotional, Social, and School
subscales as dependent variables in separate analyses. Coefficients and significance levels
were calculated for the direct, indirect, and total effects of all variables included in the
models. Indirect (i.e., mediating) effects were evaluated with 95% confidence intervals
according to both the Sobel and Monte Carlo methods. The results of both methods were
consistent; thus, we report coefficients estimated according to Sobel. The data were all
controlled for medication status, which was entered as a covariate in the model, and all
statistical analyses were performed using the Stata Software, release 16 [78].
3. Results
3.1. Clinical and Demographic Characteristics
A total of 80 participants diagnosed with TS were included in this study. The demo-
graphic data are summarized in Table 1. The mean age was 10.7 years (
±
2.3 SD), and 90%
of participants were males.
Table 1. Demographic and clinical characteristics of the study population.
Sex N(%)
Males 72 (90.0)
Females 8 (10.0)
Age
6–7 years 7 (8.8)
8–9 years 27 (33.8)
10–11 years 25 (31.3)
12–13 years 12 (15.0)
Children 2024,11, 226 7 of 18
Table 1. Cont.
14–16 years 9 (11.3)
Age
6–7 years 7 (8.8)
8–9 years 27 (33.8)
10–11 years 25 (31.3)
12–13 years 12 (15.0)
14–16 years 9 (11.3)
Familial history of tics
42 (52.5)
Pharmacological Treatment
Any treatment 14 (17.5)
SSRI 2 (2.5)
Aripiprazole 9 (11.3)
SSRI + Aripiprazole 3 (3.8)
Comorbidities
ADHD 19 (23.8)
OCD 23 (28.8)
Depression 10 (12.5)
Anxiety 21 (26.3)
ADHD + OCD 3 (3.8)
ADHD + Depression 2 (2.5)
ADHD + Anxiety 6 (7.5)
ADHD + OCD + Depression /
ADHD + OCD + Anxiety 2 (2.5)
OCD + Depression 4 (5.0)
OCD + Anxiety 10 (12.5)
Depression + Anxiety 8 (10.0)
Data presented as absolute values (percentage). SSRI = selective serotonin reuptake inhibitor.
A familial history of tic disorders was reported in 52.5% of cases. Regarding pharma-
cological treatment, 14 (17.5%) patients were already on medication—prescribed elsewhere
—at the time of evaluation: nine (11.3%) were receiving Aripiprazole for their tics, two (2.5%)
patients were on active SSRI treatment for obsessive compulsive or anxious symptomology,
and three (3.8%) were receiving combination therapy (Aripiprazole plus SSRI). Only two
children had previously received behavioral intervention for tics. As regards comorbidities,
63.8% of children presented at least one comorbidity at the time of psychiatric evaluation.
In detail, 23.8% were diagnosed with comorbid ADHD, 28.8% with OCD, 12.5% with
depression, and 26.3% with anxiety disorders. Full details on the comorbidity profiles are
listed in Table 1. The children’s psychometric data are summarized in Table 2.
Table 2. Psychometric characteristics of the sample.
YGTSS
Scores Mean SD
Total score 16.8 8.2
Motor tics 11.2 4.7
Vocal tics 5.7 5.3
Score severity N
mild (<14) 29
moderate (15–34) 50
severe (≥35) 1
Children 2024,11, 226 8 of 18
Table 2. Cont.
CY-BOCS
Scores Mean SD
Total score 7.9 7.3
Compulsions 3.1 3.9
Obsessions 4.8 4.3
Score severity N
subclinical (<8) 43
mild (8–15) 23
moderate (16–23) 11
severe (24–31) 1
extremely severe (32–40) 0
MASC
Score Mean SD
Total score 10.2 6.0
Score severity N
non-clinical (<60) 56
borderline (60–69) 11
clinical (≥70) 4
CDI
Score Mean SD N in the clinical range
Total score 10.2 6.0 16
CPRS
Scores Mean SD N in the clinical range
Oppositionality 56.6 16.1 17
Cognition 58.0 16.1 16
Hyperactivity 56.8 15.0 17
ADHD index 60.8 15.1 21
N= number of patients in absolute values.
3.2. Cognitive Performance
The mean Full-Scale Intelligence Quotient (FSIQ) score among our patients was
108 (
SD = ±15
). The FSIQ scores were between 71 and 85 in five patients (6.3%), indi-
cating borderline mental functioning. A detailed description of the WISC-IV indexes is
displayed in Table 3.
Table 3. WISC-IV mean scores, standard deviation (SD), and score range.
WISC-IV Index Mean SD Score Range
FSIQ 108 15 78–139
VCI 112 14 72–138
PRI 109 17 67–143
WMI 105 15 67–130
PSI 95 15 53–138
FSIQ: Full-Scale Intelligence Quotient, VCI: Verbal Comprehension Index, PRI: Perceptual Reasoning Index, WMI:
Working Memory Index, PSI: Processing Speed Index.
3.3. Correlations
3.3.1. Parental vs. Child YGTSS, CY-BOCS, and PEDsQoL Score Correlation
A close relation was detected between the parents’ and children’s YGTSS and CY-
BOCS (Table 4) scores, suggesting a similar perception of tic and obsessive-compulsive
symptom severity by child and family. Similarly, the children’s perception of their QoL
was comparable to that of parents filling in the proxy-report version of the questionnaire
(Table 4). Therefore, unless specified, the YGTSS, CY-BOCS, and PEDsQoL scores refer
hereinafter to those obtained from the patients only.
Children 2024,11, 226 9 of 18
Table 4. Correlations between children’s and parent’s YGTSS and CY-BOCS.
rp
YGTSS
Total score 0.49 <0.001
motor tics 0.59 <0.001
vocal tics 0.42 <0.001
impairment score 0.51 <0.001
CYBOCS
Total score 0.48 <0.001
obsessions 0.47 <0.001
compulsions 0.43 <0.001
PEDsQoL
Total score 0.52 <0.001
Physical functioning 0.53 <0.001
Emotional functioning 0.46 <0.001
Social functioning 0.49 <0.001
School functioning 0.50 <0.001
3.3.2. Correlation between Study Measures
No significant correlations were found between the YGTSS and CY-BOCS scores,
whereas such measures, when considered separately, appeared positively correlated to the
MASC and CDI scores (Table 5).
Table 5. Correlations between tic and obsessive compulsive symptom severity with CDI and MASC.
YGTSS CY-BOCS
Total Motor Tics Vocal Tics Impairment Score Total
Obsessions
Compulsions
CDI r 0.41 0.31 0.35 0.31 0.09 0.07 0.09
p<0.001 * 0.008 * 0.002 * 0.008 * 0.431 0.543 0.421
MASC total r 0.38 0.28 0.34 0.26 0.31 0.25 0.31
p0.001 * 0.017 * 0.003 * 0.026 * 0.01 * 0.033 * 0.014 *
* Significant p-value.
3.3.3. Correlation between Study Measures and Cognitive Indexes
Several significant negative correlations were detected between both age and the CPRS
subscales with the WISC indexes (Table 6). Age showed negative correlation with the total
IQ (r =
−
0.29, p= 0.009) and WMI (r =
−
0.36, p= <0.001). The total IQ was negatively
influenced by all CPRS subscales. Among these, Cognitive Problems showed the greatest
significant negative correlations with all WISC indexes, with medium correlational strength.
Table 6. Correlation between WISC indexes, CPRS subscales, and age.
WISC-IV
FSIQ VCI PRI WMI PSI
CPRS
Oppositionality r −0.29 −0.23 −0.18 −0.26 −0.28
p0.009 * 0.041 * 0.011 0.024 * 0.013 *
Cognitive Problems r −0.43 −0.29 −0.24 −0.39 −0.47
p<0.001 * 0.008 * 0.031 * <0.001 * <0.001 *
Hyperactivity r −0.34 −0.26 −0.22 −0.33 −0.32
p0.002 * 0.021 * 0.051 0.002 * 0.004 *
ADHD index r −0.37 −0.28 −0.22 −0.33 −0.45
p<0.001 * 0.012 * 0.054 0.003 * <0.001 *
AGE r−0.29 −0.20 −0.17 −0.36 −0.17
p0.009 * 0.072 0.0142 <0.001 * 0.139
* Significant p-value. FSIQ: Full-Scale Intelligence Quotient, VCI: Verbal Comprehension Index, PRI: Perceptual
Reasoning Index, WMI: Working Memory Index, PSI: Processing Speed Index.
Children 2024,11, 226 10 of 18
Only the parents’ but not patients’ CY-BOCS scores were negatively correlated with
the WMI scores (r = −0.32, p= 0.005).
A correlational analysis failed to reveal other significant variations in the WISC ac-
cording to the age at tic onset and the patient’s YGTSS, CY-BOCS, CDI, and MASC scores.
3.4. Multiple Linear Regression Analysis
To verify if comorbidities, tic severity, and disease duration were associated with
significant variations in cognitive performance in children with TS, multiple regression
analyses were conducted. The results (Table 7) showed that a greater disease duration
was predictive of a lower FSIQ (
b = −2.07
,p= 0.013), VCI (b =
−
1.97, p= 0.026), and
WMI (
b = −1.81
,p= 0.037), while greater attentive problems, as measured by the CPRS
Cognitive Problems subscale, were associated with a worse PSI (b =
−
0.42, p= 0.014).
Moreover, greater depressive symptoms predicted a lower FSIQ (b =
−
0.86, p= 0.008) and
PRI (
b = −0.89
,p= 0.02). Conversely, higher levels of anxiety symptoms as captured by
the MASC were predictive of better cognitive performance in terms of the FSIQ (b = 0.61,
p= 0.001) and all WISC subscales. The model accounted for 45% of the variance.
Table 7. Influence on the different cognitive indexes of the clinical features of TS.
FSIQ VRI PRI WMI PSI
b
(Beta) p95%
CI
b
(Beta) p95%
CI
b
(Beta) p95%
CI
b
(Beta) p95%
CI
b
(Beta) p95%
CI
TS du-
ration
years
−
2.069
(
−
0.299)
0.013 *
−
3.668
to
−
0.449
−
1.973
(
−
0.308)
0.026 *
−
3.696
to
−
0.249
−
1.649
(
−
0.216)
0.095
−
3.595
to
0.296
−
1.809
(
−
0.269)
0.037 *
−
3.507
to
−
0.112
−
0.293
(
−
0.041)
0.742
−
2.073
to
1.485
Age at
TS
onset
−
0.064
(
−
0.010)
0.931 1.531
to
1.402
−
0.452
(
−
0.074)
0.578
−
2.066
to
1.163
0.712
(0.100) 0.421
−
1.045
to
2.468
−
0.343
(
−
0.055)
0.657
−
1.883
to
1.196
−
0.523
(
−
0.079)
0.519
−
2.138
to
1.091
Sex 7.154
(0.143) 0.231 4.682
to
18.991
−
2.102
(
−
0.044)
0.748
−
15.131
to
10.927
8.715
(0.159) 0.223
−
5.461
to
22.890
3.932
(0.081) 0.529
−
8.493
to
16.356
11.476
(0.224) 0.083
−
1.555
to
24.507
Familial
history
−
1.058
(
−
0.035)
0.746 7.570
to
5.454
−
1.763
(
−
0.062)
0.624
−
8.931
to
5.405
−
1.897
(
−
0.057)
0.628
−
9.695
to
5.901
2.078
(0.071) 0.545
−
4.757
to
8.913
0.365
(0.012) 0.919
−
6.804
to
7.534
YGTSS
total 0.072
(0.039) 0.741 0.359
to
0.503
−
0.096
(
−
0.056)
0.686
−
0.571
to
0.378
0.308
(0.155) 0.237
−
0.208
to
0.824
−
0.077
(
−
0.044)
0.734
−
0.530
to
0.375
0.294
(0.158) 0.220
−
0.181
to
0.769
CYBOCS
total
−
0.163
(
−
0.082)
0.481 0.622
to
0.297
0.172
(0.092) 0.498
−
0.334
to
0.678
−
0.291
(
−
0.133)
0.294
−
0.841
to
0.259
−
0.303
(
−
0.157)
0.214
−
0.785
to
0.180
−
0.217
(
−
0.107)
0.393
−
0.723
to
0.289
CPRS
Oppo-
sition-
ality
−
0.048
(
−
0.048)
0.776 0.387
to
0.290
−
0.029
(
−
0.031)
0.876
−
0.402
to
0.343
−
0.044
(
−
0.040)
0.830
−
0.449
to
0.361
0.163
(0.168) 0.363
−
0.193
to
0.518
−
0.031
(
−
0.030)
0.869
−
0.403
to
0.342
CPRS
Cogni-
tive
Prob-
lems
−
0.170
(
−
0.161)
0.237 0.455
to
0.115
−
0.069
(
−
0.069)
0.662
−
0.382
to
0.245
−
0.006
(
−
0.006)
0.970
−
0.347
to
0.335
−
0.120
(
−
0.118)
0.426
−
0.419
to
0.179
−
0.419
(
−
0.374)
0.014 *
−
0.751
to
−
0.086
CPRS
Hyper-
activ-
ity
−
0.216
(
−
0.215)
0.205 0.554
to
0.121
−
0.206
(
−
0.217)
0.272
−
0.578
to
0.166
−
0.261
(
−
0.237)
0.201
−
0.666
to
0.143
−
0.346
(
−
0.357)
0.055
−
0.701
to
0.008
−
0.060
(
−
0.058)
0.748
−
0.432
to
0.312
CDI
total
−
0.860
(
−
0.349)
0.008 *
−
1.484
to
−
0.237
−
0.634
(
−
0.278)
0.061
−
1.297
to
0.029
−
0.893
(
−
0.328)
0.020 *
−
1.642
to
−
0.143
−
0.581
(
−
0.242)
0.080
−
1.234
to
0.072
−
0.459
(
−
0.182)
0.181
−
1.137
to
0–219
MASC
total
0.605
(0.463) 0.001 *
0.252
to
0.957
0.427
(0.353) 0.026 *
0.053
to
0.802
0.611
(0.423) 0.005 *
0.188
to
1.034
0.455
(0.358) 0.017 *
0.085
to
0.823
0.294
(0.218) 0.130
−
0.090
to
0.677
b is unstandardized and Beta is standardized regression coefficient. * Significant p-values (also highlighted in bold).
CI = confidence interval of regression coefficient b. FSIQ = Full-Scale Intelligence Quotient; VRI = Verbal Reasoning
Index; PRI = Perceptual Reasoning Index; WMI = Working Memory Index; PSI = Processing Speed Index.
3.5. Total IQ as Mediator of the Relationship between Clinical Severity of TS and QoL
Finally, based on previous results, we verified whether the overall cognitive profile
captured by the FSIQ mediated the effect on well-being perceived by the children according
to the scores given by the PEDsQoL.
As can be seen in Figure 1, the results of the mediation analysis showed that the total
effects of the CDI scores and MASC scores on the total PEDsQoL score were significant.
However, for the CDI scores, the direct effect was non-significant, thus revealing that the
effect of the CDI scores on the overall QoL was mediated completely by the FSIQ. As for
Children 2024,11, 226 11 of 18
MASC scores, these were both directly linked to a worse QoL, as well as being indirectly
associated, by means of their effect on the FSIQ, to better QoL ratings. The disease duration
was influential on QoL, but only through an indirect pathway, i.e., by having a negative
effect on the FSIQ.
Children 2024, 11, x FOR PEER REVIEW 12 of 19
Figure 1. Regression coefficients for the relationship between PEDsQoL and independent variables
of TS clinical severity as mediated by the Full-Scale Intelligence Quotient (FSIQ). * p < 0.05, ** p <
0.01.
4. Discussion
The present study offers novel insights into how different clinical features of TS
impact the cognitive functioning and QoL of children and adolescents. Our results
emphasize that in pediatric TS, depression, anxiety, and disease duration largely
contribute to both the QoL and the cognitive functioning of children, while ADHD results
in poorer cognitive performance in processing speed abilities.
Although largely associated, in the general population, with variable cognitive
deficits, particularly in executive functioning [79,80], depression in children and
adolescents with TS often remains under-recognized in clinical practice, with clinical
studies often failing to report depressive symptomatology. However, children and
adolescents with TS experience affective symptoms significantly more often than their
healthy peers [14], and up to 76% of patients aending specialist clinics show mild to
severe depressive symptoms [81]. The relationship between TS and depression appears to
be multifactorial rather than simply reactive to the frustration and distress caused by
chronic tics [81]. Our study expands the knowledge on this issue by showing that in
youngsters with TS, depression severity is predictive of a reduction in the total IQ and
processing speed index, which in turn negatively influences the QoL perceived by
children. Our findings parallel those by Hovik et al. [82] that pointed out that depression
is linked to worse cognitive performance in TS, regardless of other comorbidities.
Moreover, we highlight that depression acts on reducing the well-being of children not
only by influencing their emotional functioning, but also by impairing their cognition, a
key QoL contributor. Taking together our results and the fact that depressive symptoms
in youths with TS appear to increase over time [83], we strongly advocate for the routine
assessment and treatment of depression in children and adolescents.
The influence of anxiety on cognition and QoL in our sample was more nuanced. On
the one hand, an anxious symptomatology predicted beer IQ values and performance in
all cognitive domains except processing speed. On the other hand, the overall effect of
anxiety on QoL was negative, and this was driven by the role played by anxiety in the
emotional and social functioning of children, as revealed by our mediation analysis. The
relationship between anxiety and cognition is complex. While a large body of research has
shown its negative impact on cognitive activities [84–86], anxiety may not always interfere
with performing a demanding task, or may even be reduced by it [87–89]. Of note,
although a categorial diagnosis of any type of anxiety disorder was present in 26.3% of
cases, only 5% of our cohort reported anxiety symptoms that reached the clinical threshold
of significance according to the MASC. Therefore, the observed influence of anxiety on
cognitive performance may largely be due to subclinical anxiety levels, which seem to
FSIQ
Tic Duration
CDI
MASC
PEDsQoL
Figure 1. Regression coefficients for the relationship between PEDsQoL and independent variables of
TS clinical severity as mediated by the Full-Scale Intelligence Quotient (FSIQ). * p< 0.05, ** p< 0.01.
Regarding the different PEDsQoL subscales, only the Social Functioning and School
Functioning QoL scores were mediated by the FSIQ, whereas the Physical Functioning and
Emotional Functioning QoL subscales were not. Specifically, the CDI scores were negatively
influential on Social functioning through an indirect effect on the FSIQ, whereas the MASC
scores had a positive effect on Social and School Functioning through the effect played
on FSIQ.
The MASC and CDI scores also had a direct effect on Emotional Functioning QoL that
was independent from the FSIQ (indirect effect, non-significant).
4. Discussion
The present study offers novel insights into how different clinical features of TS impact
the cognitive functioning and QoL of children and adolescents. Our results emphasize that
in pediatric TS, depression, anxiety, and disease duration largely contribute to both the
QoL and the cognitive functioning of children, while ADHD results in poorer cognitive
performance in processing speed abilities.
Although largely associated, in the general population, with variable cognitive deficits,
particularly in executive functioning [
79
,
80
], depression in children and adolescents with
TS often remains under-recognized in clinical practice, with clinical studies often failing to
report depressive symptomatology. However, children and adolescents with TS experience
affective symptoms significantly more often than their healthy peers [
14
], and up to 76% of
patients attending specialist clinics show mild to severe depressive symptoms [
81
]. The
relationship between TS and depression appears to be multifactorial rather than simply
reactive to the frustration and distress caused by chronic tics [
81
]. Our study expands
the knowledge on this issue by showing that in youngsters with TS, depression severity
is predictive of a reduction in the total IQ and processing speed index, which in turn
negatively influences the QoL perceived by children. Our findings parallel those by Hovik
et al. [
82
] that pointed out that depression is linked to worse cognitive performance in
TS, regardless of other comorbidities. Moreover, we highlight that depression acts on
reducing the well-being of children not only by influencing their emotional functioning,
but also by impairing their cognition, a key QoL contributor. Taking together our results
and the fact that depressive symptoms in youths with TS appear to increase over time [
83
],
we strongly advocate for the routine assessment and treatment of depression in children
and adolescents.
Children 2024,11, 226 12 of 18
The influence of anxiety on cognition and QoL in our sample was more nuanced. On
the one hand, an anxious symptomatology predicted better IQ values and performance
in all cognitive domains except processing speed. On the other hand, the overall effect
of anxiety on QoL was negative, and this was driven by the role played by anxiety in the
emotional and social functioning of children, as revealed by our mediation analysis. The
relationship between anxiety and cognition is complex. While a large body of research
has shown its negative impact on cognitive activities [
84
–
86
], anxiety may not always
interfere with performing a demanding task, or may even be reduced by it [
87
–
89
]. Of note,
although a categorial diagnosis of any type of anxiety disorder was present in 26.3% of
cases, only 5% of our cohort reported anxiety symptoms that reached the clinical threshold
of significance according to the MASC. Therefore, the observed influence of anxiety on
cognitive performance may largely be due to subclinical anxiety levels, which seem to have
a positive influence on cognitive abilities. This is also in line with prior studies showing
that elevated physiological anxiety, when accompanied by low levels of worry, may predict
better IQ performance in children as well as in the elderly [
90
,
91
]. Overall, these findings
cautiously suggest that in certain tasks with high attentional demands (such as those
required by the WISC-IV), preparatory mechanisms associated with non-clinical levels
of arousal, like increased vigilance, may facilitate error monitoring and rapid response
and promote better performance [
86
,
88
]. However, our results show that, overall, anxiety
exerts a detrimental impact on the daily functioning of children with TS by reducing their
self-esteem and emotional well-being (b =
−
0.96, p= 0.007) and their perceived competence
in social interactions (b = −0.66, p= 0.001).
Unsurprisingly, our study replicates a wealth of TS studies pointing to worse cognitive
performance and lower IQ in children with concomitant ADHD and can be interpreted
similarly [
43
–
48
]. Of all cognitive domains, inattentive symptom severity was the only
clinical feature of ADHD in our cohort that significantly predicted a reduction in processing
speed. Processing speed represents the pace at which information is received, elaborated,
and replied to by the brain. This ability is important for presumably all functions, including
behavioral regulation. Indeed, in children with ADHD, reduced processing speed has been
repeatedly proposed as a useful indicator of worse behavioral functioning [
92
,
93
] and a
risk factor for later peer problems during adolescence [
94
]. Moreover, processing speed
deficits have been posited as a potential neuropsychological marker of ADHD that may
distinguish inattention due to ADHD from that due to other mental health conditions,
such as depression [
95
,
96
]. Altogether, our results suggest that assessing the cognition
in children with TS—with a particular focus on processing speed—could be even more
important in the presence of concomitant ADHD, given these implications for the cognitive
and behavioral functioning of children.
No significant role for obsessive compulsive symptoms was detected in our study, nei-
ther for cognition nor for QoL. Our results contrast a larger base of studies that point toward
better cognitive abilities in individuals with TS and comorbid OCD as compared to the
WISC norm [
46
,
97
]. However, multilayered evidence exists regarding cognitive functioning
in OCD in general. On the one hand, many studies have suggested abnormalities in cogni-
tive flexibility and memory in both patients and their unaffected relatives (e.g.,
[98–100]
);
on the other hand, data from the largest metanalysis available to date revealed no sub-
stantial cognitive impairments in children with OCD [
101
]. Such heterogeneity may have
arisen from the frequent consideration of OCD as a homogeneous condition by the extant
neuropsychological literature. Prior studies have mainly examined state severity measures
of obsessive-compulsive symptoms (e.g., the CY-BOCS) as possible moderators of patients’
cognitive performance and may have lacked consideration of the role of other clinical
factors of the disorder, such as disease duration, the type of obsessions/compulsions,
and comorbid conditions [
102
–
104
]. Further, regarding the association of TS and OCD
specifically, emerging evidence points to different neurobiological underpinnings in OCD
with TS and without it [
105
–
107
]. Hypothetically, different neural correlates of OCD in the
context of TS as compared to “pure” OCD might further be associated with differences
Children 2024,11, 226 13 of 18
in neuropsychological profiles. This possibility awaits future studies with well-defined
comorbidity profiles to increase insight into the role of OCD on cognition in children with
and without chronic tics.
Currently, it is unknown whether and how the persistence of tics, i.e., disease duration,
contributes to long-term outcomes in TS. In our study, the overall duration of tics was
independently predictive of a lower IQ, verbal reasoning, and working memory. Thus,
despite typical tic fluctuations over time and the presence of other comorbidities, children
experiencing tics over longer periods of time showed poorer cognitive abilities. Further-
more, cognitive abilities moderated the relationship between disease duration and QoL,
such that part of the effect of disease duration on well-being was mediated by the effect of
disease duration on IQ. Regarding the age at tic onset, although prior studies with different
methodologies have pointed out that an earlier TS onset may be associated with a lower
IQ [
44
,
49
], our study revealed no such effect. Therefore, the observed effect of disease
duration on cognition in our study cannot be solely attributed to an earlier age at tic onset,
but rather to the cumulative effect of having tics for greater amounts of time and, putatively,
to the persistence of disease-related biological changes and the development of higher
clinical complexity that a longer disease duration may involve. Greater consideration in
future studies of disease duration is crucially warranted to shed light on the effect of tic
persistence on cognition and functional outcomes in people with lived experience of TS.
This study should be interpreted in light of some limitations. First, we cannot exclude
that our results might be partially due to a selection bias. Specifically, the small number
of participants who reported clinical or moderate/severe symptoms of anxiety and obses-
sions/compulsions undoubtedly diminished the power of our analyses (i.e., fewer data
available on WISC scores from children with more severe symptoms). Secondly, the reduced
representation of female participants in our cohort further limits the generalizability of our
results to the overall TS population. Moreover, although we controlled our results for the
patient’s medication status (present/absent), the medication type (e.g., antipsychotics, SSRI,
both) and treatment duration were different across participants. Therefore, no conclusive
considerations can be drawn regarding their influence on cognitive profiles. Next, our
findings are based on cross-sectional analyses and, therefore, do not explain if symptom
fluctuations over time may determine different effects on the cognitive functioning of
patients in the long term. Lastly, during the clinical assessment, no systematic information
was collected on the patients’ socioeconomic statuses. Thus, it was not possible to control
the IQ scores for such an important factor [108,109].
Despite such limitations, our study is of particular use for understanding the impact of
the TS clinical spectrum on life quality. Depression deeply affects the cognitive functioning
of children living with TS. Depression also impacts on their perceived QoL through the indi-
rect effect played by depressive symptomatology on cognition. Likewise, a greater disease
duration and ADHD inattentive symptoms are both detrimental on cognitive performance,
but only disease duration was influential on children’s QoL ratings. Conversely, mild forms
of anxiety (or trait anxiety) may slightly enhance cognitive performance in TS but not QoL,
while OCD was not clearly influential on cognitive outcomes. Altogether, we highlight
that disease duration is critical for explaining the variance in cognitive performance in
TS, and that a greater duration of tics translates into a poorer perceived well-being of
children. Comorbidities, particularly depression, need to be considered as sensitive risk
factors for educational and academic underachievement [
110
] and the need for additional
support [111] in this specific population.
Based on our results, it is central for clinicians to promptly identify and quantify
comorbidities in children and adolescents with TS to start interventions aimed at their
treatment in a timely manner. This may promote a risk reduction strategy against their
detrimental consequences on cognitive functioning and overall well-being. Moreover, the
finding regarding the impact of disease duration on cognition deserves further considera-
tion in both the clinical and research fields since it raises new practical and ethical questions
about treating children and adolescents with chronic tics. There are complex issues sur-
Children 2024,11, 226 14 of 18
rounding medication use in this age group, including the consideration of when to start
medication and the potential impact of sustained medication use on the developing brain.
Still, very little is known about TS’s developmental trajectories and their determinants.
Future studies explaining why some individuals develop milder forms of TS while others
do not are critically needed to decide the timing of treatment start and end and improve
the well-being of all patients.
Author Contributions: Conceptualization, G.C. and F.C. (Francesco Cardona); methodology, G.C. and
F.C. (Francesco Cardona); formal analysis, G.C., C.C. and F.C. (Flavia Chiarotti); investigation, C.C.,
M.N., V.S., E.A., F.V. and V.B.; data curation, C.C., M.N., V.S., E.A. and F.V.; writing—original draft
preparation, G.C., C.C., M.N., V.S. and E.A.; writing—review and editing, G.C., V.B., A.T. and F.C.
(Francesco Cardona); project administration, G.C. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: This study was conducted in accordance with the Declaration
of Helsinki and approved on 17 February 2020 by the Institutional Review Board (or Ethics Committee)
of the Sapienza University of Rome (code 193).
Informed Consent Statement: Patient consent was waived due to anonymized data collection
and storage.
Data Availability Statement: The raw data supporting the conclusions of this article will be made
available upon reasonable request to the authors, without undue reservation. The data are not
publicly available due to privacy reasons.
Conflicts of Interest: All authors declare no conflicts of interest.
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