SLEEP, 2022, 1–13

https://doi.org/10.1093/sleep/zsac181
Advance Access Publication Date: 30 July 2022
Original Article

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Original Article
Down syndrome: orofacial pain, masticatory muscle hypotonia,
and sleep disorders
Bruna Dicieri-Pereira1,*, Monica Fernandes Gomes1,
Lilian Chrystiane Giannasi1, Sérgio Roberto Nacif2, Ezequiel Fernandes Oliveira1,
Miguel Angel Castillo Salgado1, José Benedito de Oliveira Amorim1,
Wagner Oliveira3, Adriano Bressane4 and Sigmar de Mello Rode3,
Center for Biosciences Applied to Patients with Special Needs (CEBAPE), Institute of Science and Technology, São José dos Campos
1

Campus, São Paulo State University (UNESP), São Paulo, Brazil, 2Hospital of the State Public Servant of São Paulo (IAMSPE), São Paulo, Brazil,
Department of Dental Materials and Prosthodontics, Institute of Science and Technology, São José dos Campos Campus, São Paulo State
3

University (UNESP), São Paulo, Brazil, 4Environmental engineering department, Institute of Science and Technology, São José dos Campos
Campus, São Paulo State University (UNESP), São Paulo, Brazil

*Corresponding author. Bruna Dicieri Pereira, Instituto de Ciência e Tecnologia, Campus de São José dos Campos, UNESP Instituto de Ciência e
Tecnologia, Campus de São José dos Campos, UNESP Avenida Engenheiro Francisco José Longo, 777 – CEP: 12.245-000, Jardim São Dimas, São José dos
Campos, São Paulo, Brazil. Email: bruna.dicieri@unesp.br, brunadicieri@gmail.com.

This analytical-descriptive study is a part of a large study protocol (Giannasi et al. [31]), entitled: “Evaluation of the masticatory muscle function, physio-
logical sleep variables, and salivary parameters after electromechanical therapeutic approaches in adult patients with Down syndrome: a randomized
controlled clinical trial”. https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3300-0. The World Health Organization Universal Trial
(UTN; number U1111-1201-3155). Registro Brasileiro de Ensaios Clínicos (ReBEC; number RBR-3qp5np).

Abstract
The aim of the present study was to investigate orofacial pain in individuals with Down syndrome (DS) and determine possible associations with masticatory
muscle hypotonia (MMH), maximum mouth opening (MMO), and sleep disorders. Twenty-three individuals with DS underwent a standardized clinical examination
using Axis I of the Diagnostic Criteria for Temporomandibular Disorders, for the diagnosis of pain in the masseter and temporal muscles and temporomandibular
joint (TMJ). MMH was investigated using electromyography of the temporal and masseter muscles and the measurement of maximum bite force (MBF). MMO
was measured using an analog caliper. Sleep disorders (obstructive sleep apnea [OSA], snoring index [SI], and sleep bruxism index [SBI]) were investigated using
type II polysomnography. Statistical analysis was performed. Nonsignificant differences were found in muscle and TMJ pain between the sexes. However, myalgia
and referred myofascial pain in the left masseter muscle were more frequent in males (69%) than females (40%). Electrical activity of the temporal (left: p = .002;
right: p = .004) and masseter (left: p = .008) muscles was significantly lower in males than in females. MBF range was lower in males than females, indicating the
highest MMH among males. OSA, SI, and SBI were identified in both sexes, but with no statistically significant differences. We concluded that myalgia and referred
myofascial pain were found in some individuals with DS, especially in males. Arthralgia was found mainly in females. Temporal and masseter myalgia may have
exerted an influence on the severity of MMH in males, particularly on the left side.

Significance
Masticatory muscle hypotonia (MMH) in individuals with Down syndrome (DS) is a predisposing factor for development of sleep dis-
orders, especially obstructive sleep apnea. This condition may intensify pre-existing cardiovascular and metabolic diseases and/or other
comorbidities in this population. Moreover, orofacial pain may exacerbate MMH, contributing to a poorer quality of life. The present study
highlights the importance of diagnosing pain experience and MMH in routine clinical practice and may help in the development of new
therapies. No previous studies have assessed pain using the Diagnostic Criteria for Temporomandibular Disorders in individuals with DS
and there is a lack of assessments of pain in youths and adults with this disease, who have difficulty expressing pain.

Key words:  down syndrome; facial pain; muscle hypotonia; masticatory muscle; temporomandibular joint; sleep-wake disorder

Submitted: 30 July, 2021; Revised: 13 July, 2022

© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights
reserved. For permissions, please e-mail: journals.permissions@oup.com

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Introduction healthy individuals. Risk factors for SB include biological (e.g.

genetic vulnerability and synaptic transmission deficit), psycho-
Down syndrome (DS) is the most common genetic disorder, and
logical (e.g. stress and anxiety), and external (e.g. alcohol abuse,
95% of causes are due to a total or partial extra copy of human
drug users, and smoker) conditions, narcolepsy, sleep disorders,
chromosome 21)  [1–3]. DS occurs in both genders and all eth-
such as OSA and snoring, as well as comorbidities, such as dia-
nicities [4]. The main phenotypic features of this condition are
betes, obesity, and hypertension. Most of these comorbidities
varying degrees of intellectual disability, congenital heart dis-
are associated with DS [20, 21]. The diagnosis of SB is confirmed
ease, immune system deficiency, decreased audio-sensory
by polysomnography (PSG).
function, muscle hypotonia, and increased maximum mouth
The literature states that the relation between orofacial

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opening (MMO) [2, 3]. Other clinical manifestations include re-
pain and sleep quality is bidirectional. Non-syndromic patients
spiratory disorders, obstructive sleep apnea (OSA), microcephaly,
have reported poor sleep quality, suggesting a negative influ-
small nasal structures and teeth, small jaw bones, a mouth
ence of pain on sleep architecture [22, 23]. The Orofacial Pain
breathing pattern, open bite, protruding tongue, periodontal dis-
Prospective Evaluation and Risk Assessment Study showed
ease, hypodontia or oligodontia, hypoplasia and/or atrophy of
that sleep quality was altered months before the onset of TMJ
major salivary glands, and temporomandibular disorders (TMD)
pain, suggesting that impaired sleep can precede orofacial pain
[2, 5–7]. According to Gomes et  al. [2], the prevalence of OSA is
[24]. Furthermore, chronic pain, including that related to TMD,
nearly 100% of youths and adults with DS.
coexists with non-restorative sleep, SB, and OSA [23]. TMD is
Masticatory muscle hypotonia (MMH) is a characteristic
very frequent and its diagnosis and treatment can be compli-
of subjects with DS that exerts a negative impact on orofacial
cated due to the lack of clarity regarding the dysfunction of the
functions, such as speech, swallowing, and chewing function [8].
trigeminal system, which can be caused by comorbidities, such
MMH causes changes in muscle tone in the oropharyngeal and
as anxiety, depression, excessive stress, and sleep disturbances
laryngeal regions, which can lead to airway obstruction during
[25].
sleep, and favor the occurrence of OSA [2, 9]. MMH alters sensory
In DS, physical conditions can facilitate the onset of pain,
information in the processing of motor responses in individuals
such as atlantoaxial instability causing spinal cord compression,
with DS, resulting in a tendency toward altered physical move-
cervical spondylosis, and hip dislocation [26, 27]. It is noteworthy
ments and stress [2, 10].
to highlight that individuals with DS have difficulty in ex-
According to the International Classification of Orofacial
pressing and reporting pain [26–28]. Authors have reported that
Pain (ICOP-I), the term TMD describes a set of painful and non-
children with DS can present involvement of the spinothalamic
painful or dysfunctional conditions that affect the masticatory
pathway, which is responsible for sensations of pain, touch, and
muscles, temporomandibular joint (TMJ), and associated struc-
temperature. These data were extracted by quantitative sen-
tures [11]. Individuals with DS may have a diagnosis of TMD, but
sorial testing and questionnaires [27]. Moreover, there is little
there is a need for further data on the condition in this popula-
knowledge about trigeminal pathways in these individuals, es-
tion [12].
pecially adults with DS.
The gold standard for the diagnosis of TMD, including
To treat pain, it is important to understand how individuals
masticatory muscle pain, is the Diagnostic Criteria for
with DS perceive it [27]. Thus, we hypothesize that orofacial
Temporomandibular Disorders (DC/TMD), which is composed of
pain could worsen MMH in DS, mitigating muscle strength
a complete history and physical examination (Axis I), psycho-
due to disuse of the masticatory muscles. This MMH could also
social assessment (Axis II), and the analysis of imaging exams,
generate greater energy and functional expenditure in this
when necessary. The DC/TMD validation project established
population. Therefore, the aim of this descriptive study was to
high sensitivity and specificity for painful musculoskeletal TMD,
investigate the presence of myalgia and arthralgia in individ-
as well as high specificity for disc displacement; thus, the DC/
uals with DS and determine relationships with MMH, MMO, and
TMD is reliable and universally accepted [13, 14].
sleep disorders in this population.
Increased MMO is correlated with arthralgia in the TMJ of indi-
viduals without DS [15, 16]. MMO is considered the gold standard
clinical exam for detecting joint hypermobility in case of aud-
Methods
ible clicks at the end of mouth opening and beginning of mouth
closure [17]. Increased MMO has been found in subjects with DS The present analytical, descriptive study is a part of a large study
compared to those without this condition [2]. Structural and func- protocol described by Giannasi et al. [29], which was registered
tional genetic factors are related to MMH, as well as muscle and in the World Health Organization Universal Trial registry (UTN;
ligament hyperlaxity [2, 18]. Joint range of motion is associated number U1111-1201-3155) and Brazilian Clinical Trials Registry
with some factors such as joint and muscle ligament hyperlaxity (ReBEC; number RBR-3qp5np). This study received approval
and increased joint hypermobility [2, 16, 17]. The DC/TMD enables from the Human Research Ethics Committees of the Institute of
the assessment of hypermobility disorders, but further studies Science and Technology of São Paulo State University (process
evaluating muscle and joint hyperlaxity are needed [2]. number 64 173 616.4.0000.0077). All legal representatives of the
Recent studies have indicated that some craniofacial ana- participants received clarifications regarding the objectives and
tomical features (including an underdeveloped middle third of procedures in simple language. Signed informed consent was
the face) combined with impaired psychosomatic development obtained with the approval of the volunteers.
may facilitate the development of TMD and sleep bruxism (SB)
in individuals with DS [12, 19].
According to Lobbezoo et  al. [20], SB is rhythmic (phasic) or
Participants
nonrhythmic (tonic) masticatory muscle activity during sleep Twenty-three male and female participants with DS of any eth-
and should not be considered a movement or sleep disorder in nicity aged 16 to 33  years, were invited to participate in this

study. We investigated the following aspects: orofacial pain,
MMH, and the prevalence and severity of sleep disorders (OSA,
snoring index [SI], and SB index [SBI]).
The inclusion criteria were satisfactory general and oral
health and preserved cognitive function to ensure the under-
standing of the simple verbal commands used to obtain the
diagnosis of pain symptoms in the masticatory muscles and
TMJ. The exclusion criteria were psychiatric disorders and con-
ditions that interfere with the understanding of simple verbal
commands, having undergone orthodontic and/or functional
orthopedic treatment, speech therapy, or physiotherapy in the
six months prior to the onset of the study, and the use of anti-
psychotics, anticonvulsants, or antidepressants due to analgesic
effects.
The participants were recruited from nonprofit and
non-governmental organizations (NGOs) that provide of social
and health care for individuals with special needs. These NGOs
are partners of the Center for Applied Biosciences for Patients
with Special Needs and the Multidisciplinary Service of Oral
Medicine for People with Disabilities. Several meetings were
held to instruct caregivers regarding the effects of this study on
the quality of life of the participants.
Protocol of study
Figure 1 displays the flowchart illustrating the study design for
the assessment of TMD (Axis I  of DC/TMD), masticatory bio-
mechanical function, and sleep disorders in individuals with DS.
Figure 1.  Flowchart of study protocol.
Pereira et al.  |  3
Analysis of orofacial pain. The DC/TMD is composed of Axes I and
II. Axis I evaluates a group of physical orofacial pain conditions,
whereas Axis II investigates psychosocial aspects. Only Axis
I was used in the present study. This axis is composed of the fol-
lowing: 1st stage—administration of two questionnaires,—one
on symptoms and the other on demographics,—to the caregiver;
2nd stage—completion a form corresponding to the functional
examination of the TMJ and extraoral physical examination of
the masticatory muscles. The DC/TMD investigates the history
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of orofacial pain and identifies the presence of orofacial signs
and symptoms related to TMD in the previous month, including
parafunctional habits, orofacial pain, headache, joint noises,
closed and open mandibular locking, recent facial trauma, and
continuous-use medications [14].
Axis I of DC/TMD—clinical examination of TMJ. Opening and closing
movements of the mouth, lateral excursions, and protrusion of
the mandible were analyzed to investigate the occurrence of
disc displacement through TMJ sounds, and ipsilateral and/or
contralateral joint and/or muscle pain during TMJ functioning
[14].
Axis I of DC/TMD—muscle and TMJ pain examinations. Pain in 2 s
of muscle palpation was diagnosed as myalgia. In cases of fa-
milial pain after 5  s of muscle palpation, the diagnosis was
local myalgia. Pain not extending beyond muscle limits but
beyond stimulation limits, within 5  s of palpation was diag-
nosed as myofascial pain with spreading. Pain exceeding the
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muscle limits within 5 s of palpation was diagnosed as referred
myofascial pain. Localized and/or modified muscle pain found
in the TMJ by the examiner was diagnosed as arthralgia [14]. The
calibration of applied pressure was 1  kg for the temporal and
masseter muscles and 0.5  kg for the TMJ region. The physical
examination (palpation) was performed in the resting position.
Axis I  of DC/TMD- headache attributed to  TMD. The diagnosis of
secondary headache required a primary diagnosis of myalgia
or arthralgia with headache in the temporal regions and in-
fluenced by mandibular movements [14]. To interpret the data
obtained during palpation, a diagnostic decision diagram was
used for the muscle subtype of TMD [14].
Analysis of masticatory biomechanical dysfunction
Masticatory biomechanical evaluation was performed to obtain
23 surface electromyography records of the masseter and tem-
poral muscles at resting conditions and using maximum volun-
tary clench (MVC, μV), oral motor tasks (using MMO [cm] and
maximum bite force intensity [MBF, kgf]). MBF was measured
using a force transducer (Filizola) and it was determined from
the deformations of a jaw force transducer’s metal bars during
bite using the Electromyography (EMG) Lab v 1.1 software (EMG
System by Brazil Ltda).
MMH was assessed using EMG recordings of the anterior por-
tion of the temporal muscles and the superficial portion of the
masseter muscles as a function of MVC and using MBF to com-
plete this diagnosis, compared to reference values of a healthy
non-syndromic control group of a previous study reported by
Gomes et  al. [2]. These values of electrical activity (EA; MVC),
and MBF in healthy non-syndromic patients are for the right
temporal (RT) (238.95  μV); left temporal (LT) (225.51  μV); right
masseter (RM) (310.18  μV); left masseter (LM) (301.26  μV); MBF
(60.53  kgf) for females; and RT (336.37  μV); LT (344.04  μV); RM
(512.24 μV); LM (580.55 μV); MBF (70.20 kgf) for males.
EMG was conducted using a device with eight input chan-
nels, (EMG-800C System do Brazil Ltda), containing a conditioner
with a band pass filter with cut-off frequencies at 20 to 500 Hz,
an amplifier gain of 1000 times, and a common-mode rejec-
tion ratio >120 dB. All data were acquired and processed using
a 16-bit analog to digital converter (software of manufacturer)
with sampling frequency of 2 kHz per channel (Figure 2A). Active
bipolar electrodes with a pre-amplification gain of 20× are in-
cluded. A  reference electrode was positioned on the patient’s
right wrist to reduce undesirable interferences of EMG signals,
which were processed using specific routines carried out in
the Matlab program, version 7.1 (The MathWorks Inc., Natick,
MA, USA).
The participants were trained to perform no orofacial move-
ments and to seat comfortably erect on a dental chair with eyes
open, feet apart, shoulders relaxed, hands resting on things, and
the head on the Frankfort plane parallel to the ground. To avoid
interferences of electrical signals and to allow a good attach-
ment of the surface electrodes on the skin, the use of disposable
medical cap, removal facial hair, and skin cleansing with the aid
of cotton soaked in 70% alcohol was done.
The intra-day and inter-day tests conducted by Giannasi
et  al. [10] demonstrated the excellent reliability of the surface
EMG variables (root mean square, mean frequency, median
frequency, and approximate entropy) of the masseter and tem-
poral muscles in adults with DS during MVC as well as good
to excellent reliability of the median and mean frequency re-
corded in the resting position, proving that EMG is a reliable re-
producible tool for the assessment of EA in this population. The
electrodes were placed on the temporal (anterior portion) and
masseter (superficial portion) muscles on both sides following
the protocols described in studies by Giannasi et al. [10, 30, 31]:
channel 1—RT; channel 2—LT; channel 3—RM; and channel 4—
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LM. Two surface electrodes were attached to each muscle (total
of eight electrodes) (Figure 2B).
MMO was measured using an analog caliper (Zahoransky).
The reference values for MMO according to Gomes et al. [2] on
average 4.01 cm for the male control group and 4.51 cm for the
female control group. Two examiners performed the EMG re-
cordings as well as the MBF and MMO in two sessions, with a
one-week interval. The sessions were held in a quiet, well-lit re-
cording room. In cases of medical or dental emergencies, the
procedures were interrupted to ensure the volunteer’s safety
and the credibility of the evaluations. All clinical procedures
were described by Gomes et al. [2]
Analysis of sleep disorders
The gold standard for the assessment of respiratory sleep dis-
orders was complete PSG—type II (PSG-II) in accordance with
the guidelines of the American Academy of Sleep Medicine
(AASM) Manual for the Scoring of Sleep and Associated Events:
Rules, Terminology and Technical Specifications (AASM Scoring
Manual, version 2.2) [32].
The PSG-II home sleep examination was performed using a
digital system (Embla; Embletta MPR PG and ST Proxy, Remlogic
Software, version 3.4.1; Natus Medical Incorporated). PSG-II was
performed in the participants’ homes during habitual sleep
time (Figure 2D–F). Twenty-three biological signals were re-
corded along with the apnea-hypopnea index (IAH), SBI, and SI.
The participants were instructed to remain relaxed and sleep
spontaneously. A technician removed the PSG equipment in the
morning and the records were interpreted by an expert. OSA
was categorized as normal (AHI: < 5/h), mild (AHI: 5 to 15/h),
moderate (AHI: >15 to 30/h), or severe (AHI: > 30/h). SB was con-
firmed when the SBI value was >2 events/h and was categorized
as mild-moderate (2 to 4 events/h) or severe (> 4 events/h) [33].
Statistical analysis
Prism 8.0 (GraphPad Software Inc.) was used to analyze the data,
which were submitted to descriptive and/or exploratory stat-
istical analysis. These analyses were performed considering a
confidence level (alpha) of 0.05—equivalent to 95% of reliability
(p ≤ .05). The sample size was not calculated, but based on pre-
vious studies [2, 8, 12]. The Shapiro-Wilk test was used to check
the normality of data distribution, and homoscedasticity was
determined using Bartlett’s test. Comparative analyses were
performed to determine statistically significant differences be-
tween the groups [34, 35]. The participants were grouped ac-
cording to sex and EMG records, muscle pain and EMG records;
TMJ pain and EMG records; Oral motor tasks and muscle pain;
oral motor tasks and TMJ pain; sleep disorders and muscle
pain; sleep disorders and TMJ pain. The same pain variables

Figure 2.  Electromyographic and polysomnographic evaluations.
Surface electromyographic device (A), surface electrodes bilaterally placed on right and left temporal and masseter muscles (B) in patients with DS (C) (D) undergoing
PSG type II home sleep test, Embletta MPR PG (E), and ST Proxy (F).
were used for the comparisons of motor oral tasks and sleep
disorders (Figures 3–17). When normality and homoscedasticity
were met, the unpaired t-test for independent samples was used
for comparisons. Otherwise, comparative analyses were con-
ducted using the Mann-Whitney test [36].
Results
The prevalence of myalgia and referred myofascial pain was
69% in the LM among the males. The prevalence of arthralgia
was 50% among females (Table 1). The diagnosis of headache
attributed to TMD was not confirmed at the end of the DC/TMD
diagnostic diagram. No signs and symptoms of TMJ disorders
were found, such as joint noises or locking during the functional
examination. Increased MMO in comparison to the control
group described in the study by Gomes et al. [2] was identified in
80% of the females and 85% of the males. MMH was confirmed
in all participants (Table 2).
Pereira et al.  |  5
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In the comparative analysis of EMG records (Figures 3–17),
the percentage of EA (%EA) was significantly lower in males for
the RT and LT muscles: RT: p = .004; LT: p = .002. %EA was signifi-
cantly lower in the LM among the males: p-value = .008 (Figure
4). No significance values were observed in the comparisons
among EMG recordings, myalgia and arthralgia (Figures 5–8,
12, 13), among oral motor tasks (MBF and MMO), myalgia and
arthralgia (Figures 9–11), or among sleep disorders, myalgia and
arthralgia (Figures 14–17). OSA, SBI, and SI were more severe in
males (38.5%, 54%, and 52.83 events/h). The mean SI was slightly
higher in males (27.6 events/h) and SBI was more frequent in
females (86.71 events/h) (Table 3).
Discussion
In our study, men with DS were more affected by myalgia, re-
ferred myofascial pain, MMH, OSA, SI, and severity of SBI. While
SBI and Arthralgia were more frequent in women. In addition,
 6 | SLEEP, 2022, Vol. 45, No. 11
Figure 3.  Electromyographic records, according to sex, (women W; men M).
Comparative analysis of electromyographic records of RT and LT muscles ac-
cording to sex, (women W; men M). RT, right temporal; LT, left temporal; %EA,
percentage of electrical activity.
Figure 4.  Electromyographic records, according to sex, (women W; men M).
Comparative analysis of the electromyographic recordings of RM and LM
muscles according to female (F) and male (M) sex. RM and LM, right and left
masseter muscles; %EA, percentage of electrical activity.
most studies have shown that the prevalence of orofacial pain is
higher in non-syndromic women [37, 38].
According to a large prospective risk assessment study [39,
40], the female sex is an important risk factor for the high preva-
lence of long-lasting pain. The reason for this prevalence re-
mains unclear, but the etiology involves genetic, psychological,
and biological factors [37]. The main genetic-biological factor
is the considerable fluctuation in estrogen level, which peaks
shortly before ovulation in women of childbearing age, who are
diagnosed with myalgia and TMJ arthralgia more often. However,
estrogen peaks can protect TMJ from degeneration [37].
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Figure 5.  Electromyographic records and myalgia.
Comparative analysis of electromyographic recordings of RT and LT muscles ac-
cording to RT and LT pain (myalgia). RT and LT, right and left temporal muscles;
%EA, percentage of electrical activity.
Figure 6.  Electromyographic records and myalgia.
Comparative analysis of the electromyographic recordings of RM and LM
muscles according to RT and LT pain (myalgia). RT and LT, right and left tem-
poral muscles; RM and LM, right and left masseter muscles; % EA, percentage
of electrical activity.
From the input of nociceptive stimuli to the receptors at the
synapse site, a region between the caudal trigeminal subnucleus
(V ofc) and the upper cervical region of the spinal cord (Vc/C1-2)
is the pathway responsible for the effects of estrogen. The Input
of nociceptive stimuli by neurons in Vc/C1-2 is linked to en-
dogenous pain pathways and autonomic modulatory pathways
[37, 38].
Psychological factors, such as somatic symptoms, psycho-
social stress, and emotional distress are predictors of an in-
crease in the prevalence of long-lasting pain [40]. Studies have
shown that women have more painful TMD, headaches, as well

Figure 7.  Electromyographic records and arthralgia.
Comparative analysis of the electromyographic recordings of RT and LT muscles
according to arthralgia (TMJ pain), bilaterally. RT and LT, right and left temporal
muscles; %EA, percentage of electrical activity, temporomandibular joint (TMJ).
Figure 8.  Electromyographic records and arthralgia.
Comparative analysis of the electromyographic recordings of RM and LM
muscles according to the arthralgia (TMJ pain), bilaterally. RM and LM, right and
left masseter muscles, %EA, percentage of electrical activity, TMJ, temporoman-
dibular joint.
as psychological and quality of life factors that exert an impact
on TMD. However, some of these studies are based on clinical
samples of individuals seeking treatment and may not repre-
sent the psychological profile of individuals with orofacial pain
in the general population [41]. It is important to remember that
depression and anxiety can cause failures in the pain modu-
lating pathway, which depends on the biopsychosocial health of
individuals, favoring long-term pain.
Estrogen exerts neuroprotective effects and playing a role
in the health of the cholinergic nervous system, with increases
in cholinergic antioxidant, and anti-inflammatory activities as
well as reductions in ischemic damage, the nonamyloidogenic
Pereira et al.  |  7
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Figure 9.  Oral motor tasks and myalgia,
Comparative analysis of oral motor tasks of maximum bite force (MBF) and max-
imum mouth opening (MMO) according to RM and LM myalgia (RM and LM pain).
RM and LM, right and left masseter muscles; MBF, maximum bite force; MMO,
maximum mouth opening.
Figure 10.  Oral motor tasks and arthralgia.
Comparative analysis of oral motor tasks of maximum bite force (MBF) and max-
imum mouth opening (MMO) according to arthralgia (TMJ pain), bilaterally. TMJ,
temporomandibular joint.
metabolism of the amyloid precursor protein, and extracellular
beta-amyloid deposition activity, which is related to Alzheimer’s
disease and dementia. Individuals with DS have a high risk of
early onset of dementia and Alzheimer’s disease. However, the
estrogen decline occurs earlier, particularly in women [38]. It
is important emphasize the role of estrogen in cognition. Our
participants have been different impaired cognitive levels, and
 8 | SLEEP, 2022, Vol. 45, No. 11
Figure 11.  Oral motor tasks and myalgia.
Comparative analysis of oral motor tasks of maximum bite force (MBF) and max-
imum mouth opening (MMO) according to RT and LT pain (myalgia). RT and LT,
right and left temporal muscles.
Figure 12.  Electromyographic records and myalgia.
Comparative analysis of electromyographic recordings of RT and LT muscles
according to RM and LM pain (myalgia). RM and LM, right and left masseter
muscles; %EA, percentage of electrical activity.
probably not had early dementia, due to de age, but showed
some intellectual disability level [42]. According to de Knegt et al.,
[43] individuals with DS and low memory scores had more pain,
and was concluded that in general, changes in cognitive func-
tion may represents an altered pain experience. In our study, the
prevalence of myalgia was higher among men with DS, probably
due to differences and fluctuations on estrogen levels in males.
Is noteworthy that there are other estrogen producer sources,
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Figure 13.  Electromyographic records and myalgia.
Comparative analysis of EMG recordings of RM and LM muscles according to RM
and LM pain (myalgia). RM and LM, right and left masseter muscles; %EA, per-
centage of electrical activity.
Figure 14.  Sleep disorders and myalgia.
Comparative analysis of sleep disorders and LM pain (myalgia). LM, left masseter
muscles; OSA, obstructive sleep apnea; SBI, sleep bruxism index; SI, snoring
index.
such as adipose tissue and supra renal glands. In the previous
study, men were more severely overweight and generally had
excessive body fat accumulation, and had more severe OSA and
MMH than women with DS [2]. One study compared cognitive
function between the sexes in adults with DS of the same age,
and men had worse outcomes than premenopausal women [42,
44]. However, few studies have compared men and women with
DS to understand the pathways that contribute to sexes differ-
ences and safer health decisions on pain and cognitive function.

Figure 15.  Sleep disorders and myalgia.
Comparative analysis of sleep disorders and RM myalgia. RM, right masseter
muscle; OSA, obstructive sleep apnea; SBI, sleep bruxism index; SI, snoring
index.
Figure 16.  Sleep disorders and myalgia.
Comparative analysis of sleep disorders according to pain: RT and LT myalgia. RT
and LT, right and left temporal muscles; OSA, obstructive sleep apnea; SBI, sleep
bruxism index; SI, snoring index.
Rare studies on orofacial pain in DS are found described
in the literature. De Knegt et al. [45] investigated whether self-
reported pain experienced in adults with DS differed from that
in non-syndromic adults. The authors concluded that not all
adults with DS and painful and/or discomfort-causing physical
conditions reported pain. This probably occurred due to com-
munication difficulties, not wanting to inconvenience others,
Pereira et al.  |  9
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Figure 17.  Sleep disorders and arthralgia.
Comparative analysis of sleep disorders according to TMJ pain (arthralgia), bi-
laterally. TMJ, temporomandibular joint; OSA, obstructive sleep apnea; SBI, sleep
bruxism index; SI, snoring index.
and/or fear of health care providers. These issues were not iden-
tified in the present study as one of the inclusion criteria was
preserved cognitive function to ensure the understanding of
verbal commands used during the administration of Axis I  of
DC/TMD. Moreover, we found that the examination was suitable
for individuals with intellectual disability because they were
submitted to the palpation directly at the pain site, enabling a
more accurate diagnosis. Therefore, Axis I  of DC/TMD demon-
strated good sensitivity and specificity for pain during the clin-
ical evaluation of our participants.
Regarding functional and excursive movements during the
administration of Axis I of DC/TMD clinical examination, all par-
ticipants were able to perform the tasks, but with different levels
of difficulty. However, some participants needed additional com-
mands to perform mandibular movements, likely due to a lack
of attention during the long-term time of examination.
The visual facial analog pain scale and numerical scale are
applied to assess intensity of pain [45, 46]. However, these tools
were not used in the present study because the participants
could respond in a biased way, depending on their momentary
emotional state. Furthermore, we believe that these individ-
uals could have difficulty in interpreting the facial expressions
on the scale and selecting numerical values corresponding to
existing pain. Thus, considering their cognitive deficiency and
deficits in understanding and communication, we recommend
Axis I of the DC/TMD for individuals with DS.
Our results showed that myalgia was more frequent in parti-
cipants with intense MMH. Moreover, the prevalence of myalgia
and referred myofascial pain was higher in the LM in males,
who also had lower values of the electromyographic signals. In
comparison to the reference values, bite force was more reduced
in the men when compared to the women with DS. Thus, we
infer that pain worsened the hypofunction of the masticatory
muscles mainly in men, leading to the disuse of these muscles.
 10 | SLEEP, 2022, Vol. 45, No. 11
Table 1.  Diagnosis using Axis I of DC/TMD—according to sex
Consequently, highly caloric pasty foods may become their pre-
ferred choice for daily meals, which is contraindicated to these
individuals, as reported the study by Gomes et al. [2]. The inges-
tion of fibrous foods could help improve MMH and is one of the
indications of support therapies.
Arthralgia exerted no interference on intensity of MMH, in
either sex.
MMO values were increased in all participants with DS
when compared to the reference values in the study by
Gomes et al. [2]. Moreover, MMO was lower in men with my-
algia. In this study, we infer that MMO was limited more
by myalgia than arthralgia. Although beyond scope of our
study, the intensity of muscle pain must also be considered.
Further investigations should be conducted to confirm this
hypothesis.
In the functional examination using Axis I  of the DC/
TMD, no signs or symptoms of joint TMD, such as TMJ noises,
were found during MMO. Researchers state that the diag-
nosis for TMJ hypermobility is characterized by TMJ noises
during MMO and/or at the beginning of mouth closure [17].
The fact that the participants of our study did not exhibit TMJ
hypermobility lends strength to the notion that increased
MMO is a genetic factor in DS, with is in agreement with
data described by Gomes et al. [2]. The authors state that the
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abnormal MMO in DS may be caused by thin collagen fibers
and/or large amount of amorphous matrix, enabling consid-
erable muscle slippage.
As a therapeutic alternative option for myalgia and arth-
ralgia in DS, orofacial muscle exercises and self-massage may
be recommended. Using the RDC/TMD, Sena et al. [12] evaluated
25 adults with DS and muscle-related TMD. The participants
were treated using orofacial muscle exercises and self-massage.
The pressure threshold upon palpation was measured using a
pressure algometer before and after the clinical intervention
to investigate pain in the masseter and temporal muscles and
TMJ. MMO was also assessed in the study. After the application
of the therapies, a significant reduction in pain was found in the
masseter and temporal muscles as well as the TMJ, bilaterally.
A nonsignificant increased in MMO was also found, lending fur-
ther strength to notion that increased MMO amplitude is a gen-
etic factor in DS.
In our study, concerning the sleep disorders, most partici-
pants had OSA, snoring, and/or SB. The severity and frequency
of these disorders was greater in the men, except for the fre-
quency of SB, which was greater in women. It is noteworthy
that the men were also more affected by myalgia and MMH. The
prevalence of myalgia and arthralgia was higher among individ-
uals with OSA when compared to those who exhibited snoring
 Pereira et al.  |  11

Table 2.  Results of the masticatory biomechanics function, according to the genders

Electrical activities (MVC; RMS, µV) MBF MMO

Patients RT (%) LT (%) RM (%) LM (%) (kgf) (%) (cm) (%)

Women 172.85 72 176.47 78 180.50 58 241.80 80 59.0 97 5.2 15

(W; 109.20 46 103.96 46 105.12 34 81.81 27 37.0 61 4.2 0
n = 10) 196.02 82 127.13 56 152.36 49 139.74 46 40.0 66 5.0 11
90.02 38 84.57 37 71.37 23 106.90 35 35.0 58 6.6 46

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164,05 69 122.29 54 170.71 55 138.93 46 48.0 79 5.3 17
237.53 99 165.89 74 150.48 48 188.81 63 55.7 92 5.3 17
77.90 37 104.14 46 81.83 26 127.65 42 28.0 46 5.6 24
88.58 37 112.86 50 120.83 39 130.54 43 58.0 96 4.1 0
161.41 68 159.73 71 147.63 48 213.60 71 53.0 87 5.6 24
106.09 44 160.66 71 175.13 56 288.26 96 46.0 76 6.0 33
Mean 140.36 59 131.77 58 135.60 44 165.80 55 45.97 MBF 5.3 MMO
SD 53.60 31.64 38.90 65.16 10.66 range: 46% 0.8 range: 0%
to 97% of to 46% of
force loss mouth
opening
gain
Men (M; 108.14 32 142.22 41 76.65 15 145.14 25 36.0 51 4.1 2
n = 13) 88.67 26 101.06 29 76.57 15 132.81 23 27.0 38 7.0 75
159.75 47 186.01 54 287.58 56 400.36 69 50.0 71 3.7 0
136.94 41 132.79 39 227.64 44 206.00 35 64.0 91 5.2 30
202.71 60 211.42 61 329.53 64 352.21 61 63.0 90 5.4 35
167.76 50 172.31 50 319.83 62 246.11 42 55.0 78 5.9 47
96.99 29 138.92 40 172.52 34 135.93 23 59.0 84 4.4 10
137.41 41 131.60 38 139.76 27 119.40 21 49.0 70 4.7 17
115.86 34 105.48 31 60.39 12 60.14 10 23.3 33 4.1 2
107.95 32 92.31 27 199.52 39 257.12 44 54.3 77 5.5 37
80.12 24 82.60 24 71.77 14 76.10 13 20.0 28 4.6 15
21.53 6 27.56 8 41.11 8 57.97 10 35.0 50 4.0 0
130.78 39 139.41 40 128.18 25 95.60 16 54.0 77 6.0 50
Mean 119.59 35 127.98 37 163.93 32 175.76 30 45.35 MBF 5.0 MMO
SD 45.19 47.81 101.58 110.00 15.24 range: 28% 1.0 range: 0%
to 91% of to 75% of
force loss mouth
opening
gain

MVC, maximum voluntary clench; RMS, root mean square; RT, right temporal; LT, left temporal; RM, right masseter; LM, left masseter; MBF, maximum bite force;
MMO, maximum mouth opening; and SD, standard deviation.
The reference values of electrical activities of the temporal and masseter muscles (right and left sides), MBF, and MMO in healthy non-syndromic patients (control
patients) were obtained from the studies of Gomes et al. [2]. See below:
Women: RT (238.95 μV); LT (225.51 μV); RM (310.18 μV); LM (301.26 μV); MBF (60.53 kgf); MMO (4.51 cm).
Men: RT (336.37 μV); LT (344.04 μV); RM (512.24 μV); LM (580.55 μV); MBF (70.20 kgf); MMO (4.01 cm).

and SB. We suggest that this occurred because OSA is associated
with MMH, according to the study of Gomes et al. [2]. According
to the literature, orofacial pain may be related to SB [15, 47, 48,
49, 50]. However, the present findings showed little relation be-
tween these disorders in DS, which may be due to the high pain
threshold in these individuals. Moreover, our findings showed
that successive snoring episodes were more frequent in indi-
viduals with myalgia, which likely occurred due to the effect of
muscle pain, accentuating MMH.
Most of the comparative analyses showed differences in
mean values between groups (men/women with and without
muscle pain and TMJ pain), but with no statistical significance.
This probably occurred due to large internal variability in the
groups as demonstrated by the very high standard deviations.
High internal variability is commonly related to effects caused
by external factors, resulting from the influence of other vari-
ables, beyond those controlled in the study. Hypothetically, the
internal variability of groups may be affected by factors such
as a wide age range, differences in overweight/obesity, as well
as heterogeneity regarding intellectual disability and MMH.
Therefore, future investigations should correlate these factors
with the phenotypic features of DS, for a more systemic and in-
clusive study.
Conclusions
In the present study, myalgia and referred myofascial pain were
found in some individuals with DS, especially males. In con-
trast, arthralgia was more prevalent among females. Temporal
and masseter myalgia may have influenced the severity of MMH
in males, particularly on the left side. Sleep disorders were more
frequent and severe in males, except for SB, which was more
frequent in females. No significant associations were found be-
tween arthralgia and MMO or among sleep disorders, myalgia,
and arthralgia.
 12 | SLEEP, 2022, Vol. 45, No. 11

Table 3.  Results of the sleep disorders, according to the genders

Patients AHI OSA Interpretation SI Snoring range SBI Interpretation

Women 45.20 *** Normal value (10%); low OSA 26.20 4.31–44.75 117.91 10% Mild to mod-
(n = 10) 14.30 * (50%); moderate OSA (20%), 44.75 4.25 erate SBI, and 40%
7.70 * and severe OSA (20%) 12.43 3.36 severe SBI
24.50 ** 4.31 0.83
4.60 N 21.19 0.57
20.90 ** 21.63 0.51

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77.70 *** 27.71 264.08
7.10 * 37.99 8.42
14.90 * 19.53 0.00
5.20 * 31.28 0.93
Mean 22.21 24.70 40.09
SD 23.02 11.78 86.71
Men (n = 13) 55.70 *** Normal value (7.6%), low OSA 52.78 5.87–52.83 0.00 23% Mild to mod-
21.40 ** (15.4%), moderate OSA 13.26 2.00 erate SBI, and 54%
3.20 N (38.5%), and severe OSA 19.64 4.77 severe SBI
11.50 * (38.5%) 5.87 44.74
10.90 * 33.60 3.78
29.30 ** 7.34 5.61
42.30 *** 52.83 1.28
30.50 *** 31.32 2.56
17.90 ** 16.96 6.78
72.50 *** 50.12 123.98
25.72 ** 28.04 0.29
96.10 *** 37.76 155.11
17.80 ** 9.93 7.45
Mean 33.45 27.65 27.57
SD 26.84   17.10 51.43

AHI, apnea and hypopnea index (events/h); OSA, obstructive sleep apnea; SI, snoring index (events/h), and SBI, sleep bruxism index (events/h).
Reference values (Sources: Gomes et al. [2] and Sateia [33]):
N normal value, * for mild OSA, ** for moderate OSA, and *** for severe OSA.

Funding 3. Chadi MJ, et al. Major salivary gland aplasia and hypoplasia

This study received funding from State of São Paulo Research
Foundation (FAPESP) - grant number 2017/06835–8.
Acknowledgments
The authors are grateful to all volunteers with Down syndrome
who participated in this study, the State of São Paulo Research
Assistance Foundation (FAPESP) for funding the study in the
form of grant number 2017/06835-8) and Marcio Tadeu Oliveria
for his exceptional support with the Embla, Embletta MPR PG
ST+PROXY, Natus equipment.
Disclosure Statement
Financial disclosure: None.
Nonfinancial disclosure: None.
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