Biomedicines 12 00671

Download as pdf or txt
Download as pdf or txt
You are on page 1of 11

biomedicines

Article
Correlation between Different Psychological Variables in
Women with Fibromyalgia with Symptoms of Neurogenic
Inflammation: A Cross-Sectional Study
Víctor Riquelme-Aguado 1,2,3,4, * , Alazne Zabarte-del Campo 4 , Guillermo Baviano-Klett 1,5,6 ,
Josué Fernández-Carnero 6,7,8,9 , Antonio Gil-Crujera 1,2 and Francisco Gómez-Esquer 1,2,6

1 Department of Basic Health Sciences, Rey Juan Carlos University, 28933 Madrid, Spain;
[email protected] (G.B.-K.); [email protected] (A.G.-C.); [email protected] (F.G.-E.)
2 Grupo de Investigación Emergente de Bases Anatómicas, Moleculares y del Desarrollo Humano de la
Universidad Rey Juan Carlos (GAMDES), 28922 Alcorcón, Spain
3 Department of Basic Medical Sciences, CEU San Pablo University, 28668 Boadilla del Monte, Spain
4 Fisioterapia Oreka CB, 45200 Illescas, Spain; [email protected]
5 Escuela Internacional de Doctorado, Department of Basic Health Sciences, Rey Juan Carlos University,
28922 Alcorcón, Spain
6 Cognitive Neuroscience, Pain and Rehabilitation Research Group (NECODOR), Faculty of Health Sciences,
Rey Juan Carlos University, 28922 Madrid, Spain; [email protected]
7 La Paz Hospital Institute for Health Research, IdiPAZ, 28029 Madrid, Spain
8 Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine,
Rey Juan Carlos University, 28922 Alcorcón, Spain
9 Grupo de Investigación de Dolor Musculoesqueletico y Control Motor, Universidad Europea de Madrid,
28670 Villaviciosa de Odón, Spain
* Correspondence: [email protected]

Abstract: Fibromyalgia (FM) is a chronic pain syndrome hypothesized to arise from a state of neu-
Citation: Riquelme-Aguado, V.; rogenic inflammation. Mechanisms responsible for pain, as well as psychological variables, are
Zabarte-del Campo, A.; Baviano-Klett, typically altered in this condition. The main objective of this research was to explore somatosensory
G.; Fernández-Carnero, J.; Gil-Crujera,
and psychological alterations in women with FM. The secondary objective was to carry out a sec-
A.; Gómez-Esquer, F. Correlation
ondary analysis to correlate the different variables studied and delve into the influences between
between Different Psychological
them. The relationship between different psychological variables in fibromyalgia is not clear in the
Variables in Women with
previous scientific literature. Forty-four individuals participated, of which twenty-two were controls
Fibromyalgia with Symptoms of
Neurogenic Inflammation: A
and twenty-two were women with fibromyalgia. The main outcome measures were the Numeric
Cross-Sectional Study. Biomedicines Pain Rating Scale, Fibromyalgia Impact Questionnaire, pressure pain threshold, conditioned pain
2024, 12, 671. https://doi.org/ modulation, anxiety and depression symptoms, catastrophizing and kinesiophobia cognitions. The
10.3390/biomedicines12030671 main analysis showed that there is a moderate correlation between the psychological variables of
depression and fear of movement and the ability to modulate pain. There is also a moderately inverse
Academic Editors: Rosanna Di Paola
correlation between pain catastrophizing cognitions and pain intensity/disability. Multiple moderate
and Roberta Fusco
and strong correlations were found among the various psychological variables studied. FM patients
Received: 21 February 2024 exhibit somatosensory alterations alongside negative psychological symptoms that influence the
Revised: 14 March 2024 experience of pain, and they may perpetuate the state of neurogenic inflammation.
Accepted: 15 March 2024
Published: 17 March 2024
Keywords: fibromyalgia; hyperalgesia; conditioned pain modulation; anxiety; depression; kinesiophobia;
catastrophism; chronic pain

Copyright: © 2024 by the authors.


Licensee MDPI, Basel, Switzerland.
This article is an open access article 1. Introduction
distributed under the terms and Fibromyalgia syndrome (FM) is a neurogenic inflammation condition characterized
conditions of the Creative Commons by chronic pain as the main symptom, associated with the presence of other symptoms
Attribution (CC BY) license (https://
of similar relevance, such as cognitive disorders, fatigue, restless sleep or the presence
creativecommons.org/licenses/by/
of psychological symptoms [1,2]. The diagnosis of FM is exclusively clinical since its
4.0/).

Biomedicines 2024, 12, 671. https://doi.org/10.3390/biomedicines12030671 https://www.mdpi.com/journal/biomedicines


Biomedicines 2024, 12, 671 2 of 11

etiology remains unknown. The clinical status of FM is heterogeneous in the population;


even in the same person, the symptoms can fluctuate daily [3]. In Madrid, Spain, 5%
of women aged 46 to 60 are affected, according to epidemiological research [4]. The
presence of psychological symptoms can aggravate the painful experience suffered by FM
patients. Both negative emotional states such as depression and the presence of cognitive
distortions such as pain catastrophizing and fear-related movement may be risk factors for
suffering from chronic pain for a longer period, increasing the intensity and the impact
on functionality [5–9]. Unfortunately, as shown in recent longitudinal epidemiological
studies [10,11], psychological symptoms have worsened owing to the health crisis caused
by the COVID-19 pandemic, which may have influenced the clinical condition of FM
patients [10,11].
Research into the pathophysiological mechanisms responsible for the pain suffered by
patients with FM is of great interest in the scientific community [12]. Several alterations in
the nociceptive system have been identified, including the transmission, processing and
modulation of painful stimuli [13–19]. One of the most relevant clinical characteristics in
patients with FM is the dysfunction in the pain inhibitory systems. It is suggested that the
endogenous capacity to modulate pain is reduced, which translates into greater central
pain processing [19].
Conditioned pain modulation (CPM) is a dynamic psychophysical test that reflects
the capacity of the descending pain modulatory systems to decrease pain [20]. The CPM
effect can be quantified by comparing the pain response to a noxious test stimulus applied
before and during (or immediately after) a noxious conditioning stimulus in another body
region. In healthy individuals, the painful conditioning stimulus should increase the
pain threshold by triggering an efficient response from the descending inhibitory system.
Nevertheless, results obtained in the CPM show great inter-individual variability, possibly
due to differences establishing CPM protocols [21,22]. The CPM test may be reliable to
demonstrate a state of neurogenic inflammation present in patients with FM. Thereby, the
dysfunction of pain inhibitory mechanisms is evident, which is characteristic of neurogenic
inflammation conditions.
On the other hand, emotional psychological symptoms such as anxiety and depression
and cognitive psychological symptoms including catastrophism or fear-related movement
are shown in neurogenic inflammation conditions [23]. Even though all these are existing
variables in patients with FM, their influence on each other remains unclear (e.g., whether
or not suffering from anxiety can trigger cognitive alterations such as fear of movement).
Furthermore, especially in patients with FM, it is unknown whether these alterations are
secondary to a state of chronic pain or whether these alterations might instead cause a
condition of neurogenic inflammation and central sensitization. The main objective of this
research was to explore somatosensory and psychological alterations in women with FM.
The secondary objective was to carry out a secondary analysis to correlate the different
variables studied and delve into the influences between them. The role of psychological
factors in FM is often studied, although the direction of the relationship remains unclear.
Given that the evidence remains weak, increasing knowledge of the relationship between
psychological aspects and somatosensory variables of pain can help improve clinical
decision-making in patients with FM and help us to find the most appropriate treatment
for each case.

2. Materials and Methods


2.1. Participants
The study involved twenty-two female FM patients (FM) and twenty-two healthy
female control subjects recruited through local support group advertisements and presenta-
tions. Data collection occurred from February to December 2023 and received approval
from the Rey Juan Carlos University Ethical Review Board (2605202012920) following
the Declaration of Helsinki. Convenience sampling method was used. All participants
provided written informed consent. Inclusion criteria for FM patients included: (1) medical
Biomedicines 2024, 12, x FOR PEER REVIEW 3 of 12
Biomedicines 2024, 12, 671 3 of 11

diagnosis
diagnosisofoffibromyalgia
fibromyalgiabybya arheumatologist
rheumatologist specialist, (2)(2)
specialist, experiencing
experiencing pain forfor
pain over 3
over
months and (3) fluency in spoken and written Spanish. The criteria of
3 months and (3) fluency in spoken and written Spanish. The criteria of speaking and speaking and un-
derstanding
understandingSpanish correctly
Spanish did not
correctly did exclude any participant
not exclude for any
any participant forethnic or social
any ethnic rea-
or social
son. A researcher
reason. A researcherwaswas
present to ensure
present that
to ensure participants
that participantsunderstood
understood the
theasked
askedtasks
tasksand
and
totoanswer
answerany
anyquestions
questionsrelated
relatedtotothe
theself-administered
self-administeredquestionnaires.
questionnaires.Exclusion
Exclusioncriteria
criteria
for
forFM
FMpatients
patientscomprised
comprisedcognitive
cognitiveinability
inabilitytotounderstand
understandor orcomplete
completemeasurement
measurement
variables.
variables. Control participants met criteria for having no pain (NPRS = 0) andfluency
Control participants met criteria for having no pain (NPRS = 0) and fluencyinin
spoken
spokenand
andwritten
writtenSpanish.
Spanish.Exclusions
Exclusionsfor forcontrol
controlsubjects
subjectsincluded
includedrecent
recent musculoskel-
musculoskele-
etal episodes within
tal pain episodes within the
thelast
last1212weeks
weeksand andanyanyrheumatologic
rheumatologicdiseases.
diseases.AAflowchart
flowchartis
isshown
shownininFigure
Figure1.1.

Study design.
Figure1.1.Study
Figure design. The
The subsequent
subsequent flowchart
flowchartillustrates
illustratesthe
theallocation
allocationofof
participants in in
participants both the
both
FMFM
the study andand
study control groups.
control Instances
groups. thatthat
Instances werewere
excluded due due
excluded to failure to meet
to failure selection
to meet criteria
selection cri-or
withdrawal
teria from the
or withdrawal investigation
from are depicted.
the investigation are depicted.

2.2.Clinical
2.2. ClinicalStatus
Status
Painintensity
Pain intensitywas
wasassessed
assessedusing
usingthe
theNumeric
NumericPainPainRating
RatingScale
Scale(NPRS),
(NPRS),aavalidated
validated
tool extensively employed for self-reported evaluation of perceived pain intensity among
tool extensively employed for self-reported evaluation of perceived pain intensity among
individuals coping with chronic pain [24]. It consists of an 11-point scale where 0 indicates
individuals coping with chronic pain [24]. It consists of an 11-point scale where 0 indicates
no pain and 10 indicates the worst pain imaginable. NPRS scores are interpreted as
no pain and 10 indicates the worst pain imaginable. NPRS scores are interpreted as fol-
follows: 0 = no pain; 1–3 = mild pain; 4–6 = moderate pain; 7–10 = severe pain. The recent
lows: 0 = no pain; 1–3 = mild pain; 4–6 = moderate pain; 7–10 = severe pain. The recent
scientific literature strongly recommends the NPRS as the foremost choice, attributing to its
scientific literature strongly recommends the NPRS as the foremost choice, attributing to
heightened sensitivity and consistent measurement of pain intensity [25].
its heightened sensitivity and consistent measurement of pain intensity [25].
The impact of FM on patients’ daily functioning and the resulting disability was
The impact of FM on patients’ daily functioning and the resulting disability was ap-
appraised using the Spanish iteration of the Fibromyalgia Impact Questionnaire (FIQ).
praised using the Spanish iteration of the Fibromyalgia Impact Questionnaire (FIQ). It is
It is composed of 10 items that allow us to assess the degree of interference from FM
composed of 10 items that allow us to assess the degree of interference from FM symptoms
symptoms in the person’s daily functioning during the last week. The first four items
in the person’s daily functioning during the last week. The first four items assess physical
assess physical function, well-being and work performance using Likert-type scales. The
function, well-being
rest of the items are and work performance
answered using a 10using Likert-type
cm visual scales.
analogue The(VAS)
scale rest ofand
the collect
items
are
information on pain, fatigue, rest quality, stiffness, anxiety and depression. Thepain,
answered using a 10 cm visual analogue scale (VAS) and collect information on score
fatigue, rest quality,
of the Likert stiffness,
scale is anxietytoand
transformed be depression.
expressed in The score of
a range the Likert
from 0 to 10.scale is trans-
In VAS, the
formed to be is
given value expressed
the scoreinfora range from 0The
each scale. to 10. In VAS,
global impactthe index
given is
value is theby
obtained score for
adding
each scale. The global
the transformed scoresimpact
on theindex is obtained
ten scales by adding
described, ranging thefrom
transformed
0 to 100, scores on the
100 being the
ten scales described, ranging from 0 to 100, 100 being the highest impairment
highest impairment caused by the syndrome. This adapted questionnaire has undergone caused by
the syndrome.
validation for This adaptedpopulation,
the Spanish questionnaire has undergone
demonstrating validation for
commendable the Spanish
sensitivity, pop-
specificity
ulation, demonstrating
and internal consistencycommendable
[26,27]. sensitivity, specificity and internal consistency
[26,27].
Biomedicines 2024, 12, 671 4 of 11

2.3. Pressure Pain Threshold (PPT)


Pressure pain threshold (PPT) is defined as the minimum pressure required, under
standardized test conditions, to elicit the slightest sensation of pain. It stands as a reli-
able gauge for evaluating pain sensitivity. A digital algometer (Model FXD 10, Wagner
Instruments, Greenwich, CT, USA) measuring pressure in kg/cm2 was employed for this
purpose. Pressure was incrementally increased on the right upper trapezius muscle at a rate
of one kilogram per second until the subject reported the sensation becoming painful. Each
measurement was conducted thrice, and the resulting mean value was used as the final
recorded measurement. This methodology has demonstrated notably high intra-examiner
reliability (ICC values = 0.97) and substantial inter-examiner reliability (ICC values = 0.79)
in the upper trapezius muscle region among healthy individuals. In individuals with FM,
this method has been validated to assess mechanical hyperalgesia, yielding an ICC value
of 0.88 [28–30].

2.4. Conditioned Pain Modulation


The cold pressor test paradigm was conducted following these steps: initially, a PPT
measurement was taken on the upper area of the right trapezius muscle, as previously
described. Subsequently, the left arm was immersed in a constant 12 ◦ C water bath for 60 s.
Finally, another PPT measurement was obtained on the upper part of the right trapezius
muscle. The Conditioned Pain Modulation (CPM) value is calculated by subtracting the
PPT value during the conditioning stimulus from the PPT value without the conditioning
stimulus. In healthy individuals whose descending inhibitory pain system works cor-
rectly, it is expected that the second algometry measurement shows increased pressure
tolerance with respect to the initial measurement before reaching the painful threshold. In
chronic pain populations and healthy individuals, the cold pressor test as a conditioning
stimulus has demonstrated favorable intra-session reliability (ICC = 0.77 and ICC = 0.64,
respectively) [31].

2.5. Psychological Variables


Psychological variables were evaluated through self-administered questionnaires,
with a researcher present throughout the process to address any inquiries from participants.
Various validated scales were employed to assess emotional and cognitive aspects, as
detailed below.

2.5.1. Depression
Depressive symptoms were assessed using the Spanish version of the Beck Depres-
sion Inventory—Second Edition (BDI-II). Each of the 21 items ranges from 0 to 3, with
63 points being the highest score, where 0 to 13 means minimal depression, 14 to 19 means
mild depression, 20 to 28 indicates moderate depression, and 29 points or more indicates
severe depression. This validated questionnaire is extensively employed in chronic pain
populations and has demonstrated strong reliability (ICC = 0.73–0.86) [32,33].

2.5.2. Anxiety
Anxiety levels were rated using the validated Spanish iteration of the Hospital Anxiety
and Depression Scale (HADS), specifically focusing on the anxiety subscale. This subset
comprises seven items, each scored from 0 to 3. A cumulative score exceeding 10 points
indicates the presence of anxiety, while a score ranging from 8 to 10 denotes a borderline
case and a score below 8 indicates an absence of significant anxiety. The reliability of this
test was found to be excellent (ICC = 0.85) [34,35].

2.5.3. Pain Catastrophizing


The Pain Catastrophizing Scale (PCS) in its Spanish version was employed to evaluate
cognitive distortions related to pain catastrophizing. This is a self-administered question-
naire consisting of 13 items with a score ranging from 0 “Not at all” to 4 “All the time”. It
Biomedicines 2024, 12, 671 5 of 11

encompasses three dimensions: helplessness (questions from 1 to 5 and 12, regarding the
person’s belief in their influence on their pain); magnification (corresponds to questions 6, 7
and 13 and refers to the exaggeration of the threatening properties of the painful stimulus);
rumination (corresponds to questions 8 to 11 and refers to the fact that the patient is unable
to stop thinking about pain, being unable to get away from the idea). A total score is
obtained (ranging from 0 to 52), so a higher score means greater pain catastrophizing. This
validated questionnaire holds substantial prominence in the scientific literature and is
widely utilized. Notably, the PCS demonstrates excellent reliability specifically among
patients with FM, showing an ICC value of 0.94 [36].

2.5.4. Fear-Related Movement


The assessment of cognitive distortions related to fear of movement (kinesiophobia)
was conducted using the Spanish version of the Tampa Kinesiophobia Scale (TSK-11). It is
an 11-item scale, each with 4 possible answers, where “totally disagree” obtains 1 point
and “totally agree” obtains 4 points. Therefore, the total score ranges from 11 to 44 points, a
high score being indicative of greater fear of movement/injury, that is, high levels of fear of
movement. This scale has been extensively employed among individuals enduring chronic
pain, including those with FM, exhibiting commendable psychometric properties with an
ICC of 0.85 [37,38].

2.6. Statistical Analysis


The data analysis employed the Statistics Package for Social Science (SPSS 25.00,
IBM Chicago, IL, USA) with a 95% confidence interval (95% CI), considering p-values
below 0.05 as statistically significant. To compare differences among nominal variables
(e.g., profession or marital status), the Chi-square test was utilized across groups, each
consisting of twenty-two participants. Normality tests, specifically the Shapiro–Wilk
and Kolmogorov–Smirnov tests, were conducted, revealing no statistically significant
differences indicating an abnormal distribution within the data sets. For the comparison of
continuous variables between groups, the Student’s t-test for independent samples was
applied as the statistical test. Subsequently, Cohen’s d was calculated to assess the effect size
of the study variables, categorized as small (0.20–0.49), medium (0.50–0.79) or large (>0.8)
according to Cohen’s criteria. The correlation between psychological variables (depression,
anxiety, catastrophizing and fear-related movement) and psychophysiological measures
(CPM, PPT, FIQ and NPRS) was examined using the Pearson correlation coefficient. A
correlation coefficient >0.60 indicated a strong correlation; a coefficient between 0.30 and
0.60 indicated a moderate correlation and a coefficient <0.30 indicated a low correlation. A
significance level of p < 0.05 was set for all statistical tests conducted during the analysis.

3. Results
3.1. Clinical Status of FM Patients and Pain-Free Controls
Twenty-two participants were pain-free women controls (with a mean age of
48.55 ± 8.19 years), and twenty-two patients were women diagnosed with FM
(52.05 ± 8.35 years). According to the FIQ, patients had on average mildly severe symp-
toms and severe function deficits with 86.49 ± 3.62. The mean pain intensity was 6.05/10
(SD ± 1.88). There were no statistically significant differences between healthy subjects and
patients according to the sociodemographic variables shown in Table 1.

3.2. Mechanical Hyperalgesia and Conditioned Pain Modulation


Patients with FM presented a reduced PPT, which is indicative of mechanical hyper-
algesia (t = 6.5; p < 0.001; d = 0.53), as well as showing lower values in the CPM (t = 7.8;
p < 0.001; d = 0.64), which indicates alterations in the functioning of the descending pain
inhibitory system. Data are shown in Table 2.
Biomedicines 2024, 12, 671 6 of 11

Table 1. Descriptive statistics in demographic measures (n = 44).

FM Pain-Free Controls p Value-Independent


Measures
(n = 22) (n = 22) Sample Student t-Test
Age 52.05 ± 8.35 48.55 ± 8.19 0.84
Pain (NPRS) 6.05 ± 1.88 not measured not measured
FIQ 86.49 ± 3.62 not measured not measured
Data are presented as means (SD). Patients in the FM sample present high values of clinical pain intensity on
the Numeric Pain Rating Scale (NPRS) and high levels of impact of the disease measured with the Fibromyalgia
Impact Questionnaire (FIQ). FIQ and NPRS were administered only to FM participants. FM = Fibromyalgia;
NPRS = Numeric Pain Rating Scale; FIQ = Fibromyalgia Impact Questionnaire.

Table 2. Between-group comparison in psychophysiological measures.

FM Pain-Free Controls p Value Independent


Measures T Values
(n = 22) (n = 22) Sample Student t-Test
PPT 2.21 ± 0.04 3.21 ± 0.63 0.001 * 6.5
CPM 0.01 ± 0.78 1.5 ± 0.46 0.001 * 7.8
This table shows differences between groups in psychophysiological measures of PPT (pressure pain threshold)
and CPM (conditioned pain modulation). The FM group has reduced PPT, indicative of mechanical hyperalgesia
and decreased activation of the descending pain inhibitory system. * Indicates values with a p-value inferior to 0.05
(statistically significant). FM = Fibromyalgia; PPT = pressure pain threshold; CPM = conditioned pain modulation.

3.3. Anxiety, Depression, Fear-Related Movement and Pain Catastrophism


The independent sample Student’s t-test revealed significant inter-group differences.
Patients with FM had higher scores on the HADS anxiety subscale (t = 4.3; p < 0.001; higher
scores on the BDI-II (t = 18.25; p < 0.0001, d = 5.8); d = 2.9), higher scores on the PCS (t = 16.1;
p < 0.01; d = 3.8) and higher scores on the TSK-11(t = 7.4; p < 0.01; d = 7.01) compared to the
control group. Data are shown in Table 3.

Table 3. Between-group comparison in anxiety, depression, fear-related movement and pain catastro-
phizing psychological variables.

FM Pain-Free Controls p Value Independent


Measures T Values
(n = 22) (n = 22) Samples Student t-Test
Anxiety 11.09 ± 3.02 7.28 ± 2.6 0.001 * 4.3
BDI (II) 37.27 ± 0.7.9 9.86 ± 0.2.1 0.001 * 18.25
Pain catastrophizing 34.11 ± 3.7 15.14 ± 4.02 0.001 * 16.1
Fear-related movement 31.32 ± 3.61 15.27 ± 9.10 0.001 * 7.4
This table show differences between groups in psychological variables of anxiety, pain catastrophism. * In-
dicates values with a p-value inferior to 0.05 (statistically significant). FM = fibromyalgia; BDI II = Beck
Depression Inventory.

3.4. Correlation Analysis


After examining the bivariate relationships between somatosensory and psychological
variables, statistically significant correlations were found. Results are shown in Table 4.

Table 4. Correlation coefficients between somatosensory and psychological variables.

Measures Depression Anxiety Pain Catastrophizing Fear-Related Movement


NPRS −0.06 0.04 −0.34 * −0.1
FIQ 0.22 0.14 −0.3 * −0.02
PPT −0.02 0.14 0.09 −0.08
CPM 0.36 * 0.26 −0.08 0.30 *
Anxiety 0.64 * - 0.51 * 0.54 *
Depression - 0.64 * 0.21 0.61 *
Pain catastrophizing 0.2 0.51 * - 0.60 *
Fear-related movement 0.61 * 0.54 * 0.60 * -
This table shows correlation coefficients between somatosensory and psychological variables. * Indicates values
with correlation. Coefficient > 0.60 indicated a strong correlation; coefficient between 0.30 and 0.60 indicated a
moderate correlation; coefficient < 0.30 indicated a low correlation.
Biomedicines 2024, 12, 671 7 of 11

4. Discussion
The main objective of this research was to explore somatosensory and psychological
alterations in women with FM. The secondary objective was to carry out a secondary analysis
to correlate the different variables studied and delve into the influences between them.
Women with FM displayed mechanical hyperalgesia and reduced capacity to modu-
late pain compared to the control group, which is characteristic of populations experiencing
chronic pain. Moreover, females with FM display adverse emotional symptoms such as
anxiety and depression alongside cognitive distortions related to pain catastrophizing and
fear of movement when compared to healthy controls. Depression symptoms exhibited a
moderate correlation with pain modulation capacity and a strong correlation with emo-
tional symptoms of anxiety and cognitive distortion related to fear of movement. Anxiety
demonstrated a strong correlation with depression, as well as with cognitive distortions
regarding pain catastrophizing and fear-related movement. Pain catastrophizing cognitions
exhibited a moderate negative correlation with pain intensity (NPRS) and disability (FIQ),
whereas they displayed a strong correlation with emotional symptoms of anxiety and cogni-
tive distortions related to fear of movement. Furthermore, fear-related cognitive distortions
showed a moderate correlation with altered functioning of pain inhibitory systems, as well
as a strong correlation with the presence of negative emotional symptoms of depression
and anxiety and pain-related catastrophic cognitions.

4.1. Correlations between Somatosensory and Psychological Variables


Patients with FM experience moderate to severe levels of pain intensity and disability.
According to Tabach Apraiz et al., the average level of pain intensity is 7.29 [39]. Regarding
the validation study of the FIQ, the mean scores may vary depending on the authors (Rivera
and González’s study scored 52, whereas Monterde et al. set it at 70.8) [27,40].
In our study, through a secondary correlation analysis, we observed that patients
exhibiting higher levels of catastrophizing subsequently reported lower levels of pain
intensity and disability. Being that this finding is likely to be surprising, the prior scientific
literature warns about potential biases among FM patients in self-administered question-
naires, particularly those undergoing legal processes, as highlighted in the study by Capilla
Ramirez et al. [41]. Previous scientific evidence demonstrates that patients with FM in
ongoing legal litigation are more consistent in their responses regarding different disability
and psychological questionnaires or general health status. Conversely, as shown in the
validation study of the FIQ in the Spanish population, those who do not have pending
legal litigation do not show such a marked consistency in their responses between ques-
tionnaires [40]. Our study shows that catastrophizing pain exaggeration traits does not
always correlate with other scales measuring pain intensity or disability in patients with
FM. Furthermore, no correlation has been found between high scores on the HADS anxiety
questionnaire, higher pain intensity levels (NPRS) and mechanical hyperalgesia (PTT).
Previous scientific evidence suggests that patients with anxiety symptoms present greater
activation of the medial prefrontal cortex, which is involved in the emotional aspects of
pain while they are under a painful stimulus. Nonetheless, our study does not report higher
NPRS scores in baseline situations where there was not a painful stimulation, nor when
measurements were made with the PPT [42]. These findings suggest that even though
patients with FM present high anxiety levels, these symptoms do not influence the detection
of mechanical stimuli nor the pain levels reported (NPRS) in rest situations.
In different populations suffering from chronic pain, the CPM test shows reduced activity
of descending inhibitory systems [43]. In addition, reduced CPM is also associated with pain
in more body regions [44], as could be the case of patients with FM. Owing to the influence of
the prefrontal cortex (PFC) and the anterior cingulate cortex (ACC) on the emotional response
to pain and pain behaviors, it is hypothesized that psychological factors such as depression or
pain catastrophizing can influence the ability to modulate pain [45–47]. Conflicting results
have been reported regarding the correlation between psychological factors and CPM, both
in healthy subjects and in those suffering from chronic pain [48,49]. There is evidence of
Biomedicines 2024, 12, 671 8 of 11

alterations in the CPM in patients with FM [19], although the scientific literature is scarce
when it comes to how psychological variables can influence the ability to modulate pain
measured with the CPM paradigm [50]. According to our findings, depression and fear-
related movement moderately correlate with reduced functioning of inhibitory systems. In
our work, the cold thermal stimulus was used to trigger the conditioning stimulus. It must
be considered that there are other methods used to provoke the conditioning stimulus in the
CPM test, such as thermal heat stimuli, electrical stimuli or ischemic stimuli. Future studies
should evaluate how the psychological variables of patients with FM influence the CPM test
performed with different conditioning stimuli.

4.2. Correlations between Different Psychological Variables


Previous scientific evidence has found psychological alterations in patients with
FM, although the relationship between them lacks certainty. Increasing knowledge of this
relationship can help make clinical decisions in each case. Our findings regarding emotional
psychological variables (anxiety and depression) align with the prior scientific literature,
as demonstrated in the recent study by Henao-Perez et al. [51] One of the remarkable
features of our work involves conducting a secondary analysis to delve into the correlation
between psychological variables. Our results provide evidence of a strong correlation
between anxiety and depression, indicating their frequent co-occurrence in FM patients.
Additionally, a moderate correlation was found between heightened anxiety levels and
cognitive distortions related to pain catastrophizing or fear of movement. Depressive
symptoms exhibited a stronger correlation with fear of movement but not with pain
catastrophizing cognitions.
With regard to cognitive psychological variables, our findings also align with the prior
scientific literature, revealing cognitive distortions of pain catastrophizing and kinesiopho-
bia in patients with FM. Furthermore, in the secondary correlation analysis, our results
agree with those introduced by Koçyigit et al. [9], who found a correlation between kine-
siophobia, depression and functional disability (FIQ). In our current study, we observed a
correlation between kinesiophobia and other psychological variables (anxiety, depression
and catastrophizing), but not with disability. Finally, regarding pain catastrophizing, our
results are consistent with the prior scientific literature, indicating elevated levels of pain
catastrophizing among women with FM. In this regard, the previous scientific literature
has also linked pain catastrophizing with lower levels of physical activity and increased
fatigue [52].

4.3. Limitations
The primary limitation refers to the absence of blinding among evaluators conducting
measurements, resulting in knowledge of participants’ group allocations. Secondly, this
study did not assess the medications administered to patients, potentially impacting the
outcomes. Lastly, this study encountered a reduced sample size. Future studies that
have a larger sample size will study the influences between the variables through linear
regression analysis.

4.4. Applications for Clinical Practice


The findings of this investigation allow us to better understand the correlation between
psychological symptoms and somatosensory variables, as well as the correlations among
various psychological factors in FM patients. Thereby, it is suggested that patients with
FM who have high depressive symptoms or fear of movement are likely to lack the ability
to modulate pain, which must be taken into account when prescribing their treatment.
For instance, it is known that physical exercise activates the descending pain inhibitory
system. However, when prescribed to patients with FM, their fear of movement can play
an important role; being gradually exposed to physical exercise is required to carry out
their treatment.
Biomedicines 2024, 12, 671 9 of 11

4.5. Future Lines of Research


We suggest conducting future longitudinal studies periodically assessing changes
in somatosensory and psychological variables in women with FM. This approach would
enable a more accurate identification of the interaction between these variables during
the course of the disease. Also, future longitudinal studies that subclassify patients with
FM and identify the best treatments according to the variables affected in each case are
encouraged. Finally, in accordance with the line of research of our research group, it seems
appropriate to carry out studies where implicit motor imagery is used in the early stages as
a pain treatment technique in patients with FM, since, according to our previous studies,
implicit motor imagery is related to the dysfunction of their pain inhibitory systems [53,54].
Consequently, as its implementation does not evoke painful sensations, nor is it influenced
by the psychological aspects in patients with FM, we hypothesize that it could enhance their
pain coping and subsequently, secondarily influence psychological symptom improvement.

5. Conclusions
Depression and fear-related movement are two psychological variables that can influ-
ence pain modulation in patients with fibromyalgia. The correlations between the different
psychological variables must be taken into account in the clinical setting.

Author Contributions: Conceptualization, V.R.-A., A.G.-C. and F.G.-E.; methodology, V.R.-A., A.G.-
C., F.G.-E. and J.F.-C.; data curation, V.R.-A., A.G.-C., J.F.-C. and F.G.-E.; writing—original draft
preparation, V.R.-A., A.G.-C., F.G.-E. and A.Z.-d.C.; writing—review and editing, V.R.-A., A.G.-C.,
F.G.-E., J.F.-C., G.B.-K. and A.Z.-d.C.; supervision, A.G.-C. and F.G.-E.; project administration, V.R.-A.,
A.G.-C. and F.G.-E. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was approved by the Ethical Review Board of the
Rey Juan Carlos University (2605202012920) in accordance with the Declaration of Helsinki.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: Data are contained within the article.
Acknowledgments: AFYNSYFACRO (fibromyalgia association in Móstoles, Spain).
Conflicts of Interest: The authors declare no conflicts of interest.

References
1. Wolfe, F.; Brähler, E.; Hinz, A.; Häuser, W. Fibromyalgia Prevalence, Somatic Symptom Reporting, and the Dimensionality of
Polysymptomatic Distress: Results From a Survey of the General Population. Arthritis Care Res. 2013, 65, 777–785. [CrossRef]
2. Silverman, S.L.; Harnett, J.; Zlateva, G.; Mardekian, J. Identifying Fibromyalgia-Associated Symptoms and Conditions from a
Clinical Perspective: A Step toward Evaluating Healthcare Resource Utilization in Fibromyalgia. Pain Pract. 2010, 10, 520–529.
[CrossRef]
3. Finan, P.H.; Zautra, A.J.; Davis, M.C.; Lemery-Chalfant, K.; Covault, J.; Tennen, H. COMT Moderates the Relation of Daily
Maladaptive Coping and Pain in Fibromyalgia. Pain 2011, 152, 300–307. [CrossRef] [PubMed]
4. Regal Ramos, R.J. Epidemiological Characteristics of Patients Evaluated with Fibromyalgia in the Assessment of Disability Unit
of Madrid. Semergen 2017, 43, 28–33. [CrossRef]
5. Lee, J.; Protsenko, E.; Lazaridou, A.; Franceschelli, O.; Ellingsen, D.M.; Mawla, I.; Isenburg, K.; Berry, M.P.; Galenkamp, L.;
Loggia, M.L.; et al. Encoding of Self-Referential Pain Catastrophizing in the Posterior Cingulate Cortex in Fibromyalgia. Arthritis
Rheumatol. 2018, 70, 1308–1318. [CrossRef] [PubMed]
6. Bernik, M.; Sampaio, T.P.A.; Gandarela, L. Fibromyalgia Comorbid with Anxiety Disorders and Depression: Combined Medical
and Psychological Treatment. Curr. Pain Headache Rep. 2013, 17, 358. [CrossRef]
7. Giesecke, T.; Williams, D.A.; Harris, R.E.; Cupps, T.R.; Tian, X.; Tian, T.X.; Gracely, R.H.; Clauw, D.J. Subgrouping of Fibromyalgia
Patients on the Basis of Pressure-Pain Thresholds and Psychological Factors. Arthritis Rheum. 2003, 48, 2916–2922. [CrossRef]
[PubMed]
8. Leon-Llamas, J.L.; Murillo-Garcia, A.; Villafaina, S.; Domínguez-Muñoz, F.J.; Morenas, J.; Gusi, N. Relationship between
Kinesiophobia and Mobility, Impact of the Disease, and Fear of Falling in Women with and without Fibromyalgia: A Cross-
Sectional Study. Int. J. Environ. Res. Public Health 2022, 19, 8257. [CrossRef]
Biomedicines 2024, 12, 671 10 of 11

9. Koçyiğit, B.F.; Akaltun, M.S. Kinesiophobia Levels in Fibromyalgia Syndrome and the Relationship Between Pain, Disease
Activity, Depression. Arch. Rheumatol. 2020, 35, 214–219. [CrossRef]
10. Haider, S.; Janowski, A.J.; Lesnak, J.B.; Hayashi, K.; Dailey, D.L.; Chimenti, R.; Frey-Law, L.A.; Sluka, K.A.; Berardi, G. A
Comparison of Pain, Fatigue, and Function between Post-COVID-19 Condition, Fibromyalgia, and Chronic Fatigue Syndrome: A
Survey Study. Pain 2022, 164, 385–401. [CrossRef]
11. Lazaridou, A.; Paschali, M.; Vilsmark, E.S.; Wilkins, T.; Napadow, V.; Edwards, R. The Impact of COVID-19 Pandemic on Mental
and Physical Wellbeing in Women with Fibromyalgia: A Longitudinal Mixed-Methods Study. BMC Women’s Health 2022, 22, 267.
[CrossRef] [PubMed]
12. Gyorfi, M.; Rupp, A.; Abd-Elsayed, A. Fibromyalgia Pathophysiology. Biomedicines 2022, 10, 3070. [CrossRef] [PubMed]
13. Serra, J.; Collado, A.; Solà, R.; Antonelli, F.; Torres, X.; Salgueiro, M.; Quiles, C.; Bostock, H. Hyperexcitable C Nociceptors in
Fibromyalgia. Ann. Neurol. 2014, 75, 196–208. [CrossRef] [PubMed]
14. Desmeules, J.A.; Cedraschi, C.; Rapiti, E.; Baumgartner, E.; Finckh, A.; Cohen, P.; Dayer, P.; Vischer, T.L. Neurophysiologic
Evidence for a Central Sensitization in Patients with Fibromyalgia. Arthritis Rheum. 2003, 48, 1420–1429. [CrossRef]
15. Gracely, R.H.; Ambrose, K.R. Neuroimaging of Fibromyalgia. Best Pract. Res. Clin. Rheumatol. 2011, 25, 271–284. [CrossRef]
16. Kaplan, C.M.; Schrepf, A.; Vatansever, D.; Larkin, T.E.; Mawla, I.; Ichesco, E.; Kochlefl, L.; Harte, S.E.; Clauw, D.J.;
Mashour, G.A.; et al. Functional and Neurochemical Disruptions of Brain Hub Topology in Chronic Pain. Pain 2019, 160, 973–983.
[CrossRef]
17. Staud, R.; Domingo, M. Evidence for Abnormal Pain Processing in Fibromyalgia Syndrome. Pain Med. 2001, 2, 208–215. [CrossRef]
18. Harris, R.E.; Clauw, D.J.; Scott, D.J.; McLean, S.A.; Gracely, R.H.; Zubieta, J.-K. Decreased Central Mu-Opioid Receptor Availability
in Fibromyalgia. J. Neurosci. 2007, 27, 10000–10006. [CrossRef]
19. O’Brien, A.T.; Deitos, A.; Triñanes Pego, Y.; Fregni, F.; Carrillo-de-la-Peña, M.T. Defective Endogenous Pain Modulation in
Fibromyalgia: A Meta-Analysis of Temporal Summation and Conditioned Pain Modulation Paradigms. J. Pain 2018, 19, 819–836.
[CrossRef]
20. Nir, R.-R.; Yarnitsky, D. Conditioned Pain Modulation. Curr. Opin. Support. Palliat. Care 2015, 9, 131–137. [CrossRef] [PubMed]
21. Firouzian, S.; Osborne, N.R.; Cheng, J.C.; Kim, J.A.; Bosma, R.L.; Hemington, K.S.; Rogachov, A.; Davis, K.D. Individual
Variability and Sex Differences in Conditioned Pain Modulation and the Impact of Resilience, and Conditioning Stimulus Pain
Unpleasantness and Salience. Pain 2020, 161, 1847–1860. [CrossRef]
22. Vaegter, H.B.; Petersen, K.K.; Mørch, C.D.; Imai, Y.; Arendt-Nielsen, L. Assessment of CPM Reliability: Quantification of the
within-Subject Reliability of 10 Different Protocols. Scand. J. Pain 2018, 18, 729–737. [CrossRef]
23. Meade, E.; Garvey, M. The Role of Neuro-Immune Interaction in Chronic Pain Conditions; Functional Somatic Syndrome,
Neurogenic Inflammation, and Peripheral Neuropathy. Int. J. Mol. Sci. 2022, 23, 8574. [CrossRef]
24. Ferreira-Valente, M.A.; Pais-Ribeiro, J.L.; Jensen, M.P. Validity of Four Pain Intensity Rating Scales. Pain 2011, 152, 2399–2404.
[CrossRef] [PubMed]
25. Euasobhon, P.; Atisook, R.; Bumrungchatudom, K.; Zinboonyahgoon, N.; Saisavoey, N.; Jensen, M.P. The Reliability and
Responsivity of Pain Intensity Scales in Individuals with Chronic Pain. Pain 2022, 163, e1184–e1191. [CrossRef] [PubMed]
26. Casanueva, B.; García-Fructuoso, F.; Belenguer, R.; Alegre, C.; Moreno-Muelas, J.V.; Hernández, J.L.; Pina, T.; González-Gay, M.Á.
The Spanish Version of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia: Reliability
and Validity Assessment. Clin. Exp. Rheumatol. 2016, 34, S55–S58. [PubMed]
27. Rivera, J.; González, T. The Fibromyalgia Impact Questionnaire: A Validated Spanish Version to Assess the Health Status in
Women with Fibromyalgia. Clin. Exp. Rheumatol. 2004, 22, 554–560. [PubMed]
28. Walton, D.M.; Macdermid, J.C.; Nielson, W.; Teasell, R.W.; Chiasson, M.; Brown, L. Reliability, Standard Error, and Minimum
Detectable Change of Clinical Pressure Pain Threshold Testing in People with and without Acute Neck Pain. J. Orthop. Sports
Phys. Ther. 2011, 41, 644–650. [CrossRef]
29. Cheatham, S.W.; Kolber, M.J.; Mokha, G.M.; Hanney, W.J. Concurrent Validation of a Pressure Pain Threshold Scale for Individuals
with Myofascial Pain Syndrome and Fibromyalgia. J. Man. Manip. Ther. 2018, 26, 25–35. [CrossRef] [PubMed]
30. Nussbaum, E.L.; Downes, L. Reliability of Clinical Pressure-Pain Algometric Measurements Obtained on Consecutive Days. Phys.
Ther. 1998, 78, 160–169. [CrossRef]
31. Nuwailati, R.; Bobos, P.; Drangsholt, M.; Curatolo, M. Reliability of Conditioned Pain Modulation in Healthy Individuals and
Chronic Pain Patients: A Systematic Review and Meta-Analysis. Scand. J. Pain 2022, 22, 262–278. [CrossRef]
32. Sanz, J. Adaptación Española Del Inventario Para La Depresión de Beck-II (BDI-II): 3. Propiedades Psicométricas En Pacientes
Con Trastornos Psicológicos Spanish Adaptation of the Beck Depression Inventory-II (BDI-II): 3. Psychometric Features in Patiens
with Psychological Disorders. Clínica y Salud 2005, 16, 121–142.
33. Wiebe, J.S.; Penley, J.A. A Psychometric Comparison of the Beck Depression Inventory-II in English and Spanish. Psychol. Assess.
2005, 17, 481–485. [CrossRef]
34. Herrero, M.J.; Blanch, J.; Peri, J.M.; De Pablo, J.; Pintor, L.; Bulbena, A. A Validation Study of the Hospital Anxiety and Depression
Scale (HADS) in a Spanish Population. Gen. Hosp. Psychiatry 2003, 25, 277–283. [CrossRef] [PubMed]
35. Ryde-Brandt, B. Anxiety and Depression in Mothers of Children with Psychotic Disorders and Mental Retardation. Br. J. Psychiatry
1990, 156, 118–121. [CrossRef]
Biomedicines 2024, 12, 671 11 of 11

36. García Campayo, J.; Rodero, B.; Alda, M.; Sobradiel, N.; Montero, J.; Moreno, S. Validación de La Versión Española de La Escala
de La Catastrofización Ante El Dolor (Pain Catastrophizing Scale) En La Fibromialgia. Med. Clin. 2008, 131, 487–493. [CrossRef]
[PubMed]
37. Larsson, C.; Ekvall Hansson, E.; Sundquist, K.; Jakobsson, U. Kinesiophobia and Its Relation to Pain Characteristics and Cognitive
Affective Variables in Older Adults with Chronic Pain. BMC Geriatr. 2016, 16, 128. [CrossRef] [PubMed]
38. Salvador, E.M.E.S.; Franco, K.F.M.; Miyamoto, G.C.; Franco, Y.R.D.S.; Cabral, C.M.N. Analysis of the Measurement Properties of
the Brazilian-Portuguese Version of the Tampa Scale for Kinesiophobia-11 in Patients with Fibromyalgia. Braz. J. Phys. Ther. 2021,
25, 168. [CrossRef] [PubMed]
39. Tabach Apraiz, A.D.; Oyanadel Maldonado, M.L.; Gutierrez Espinoza, H.; Bueno Buker, D. Correlación Entre Oportunidad
Diagnóstica y Severidad Del Dolor En Pacientes Con Fibromialgia Que Ingresan a La Unidad de Dolor Crónico No Oncológico
En Hospital Clínico San Borja Arriarán. Rev. Soc. Española Dolor 2019, 26, 331–336. [CrossRef]
40. Monterde, S.; Salvat, I.; Montull, S.; Fernández-Ballart, J. Validación de La Versión Española Del Fibromyalgia Impact Question-
naire. Rev. Española Reumatol. 2004, 31, 507–513.
41. Capilla Ramírez, P.; González Ordi, H.; Santamaría Fernández, P.; Pérez Nieto, M.Á.; Casado Morales, M.I. Fibromialgia:
¿exageración o Simulación? Clin. Salud 2013, 24, 185–195. [CrossRef]
42. Ochsner, K.N.; Ludlow, D.H.; Knierim, K.; Hanelin, J.; Ramachandran, T.; Glover, G.C.; Mackey, S.C. Neural Correlates of
Individual Differences in Pain-Related Fear and Anxiety. Pain 2006, 120, 69–77. [CrossRef]
43. Lewis, G.N.; Rice, D.A.; McNair, P.J. Conditioned Pain Modulation in Populations with Chronic Pain: A Systematic Review and
Meta-Analysis. J. Pain 2012, 13, 936–944. [CrossRef]
44. Vaegter, H.B.; Graven-Nielsen, T. Pain Modulatory Phenotypes Differentiate Subgroups with Different Clinical and Experimental
Pain Sensitivity. Pain 2016, 157, 1480–1488. [CrossRef]
45. Goffaux, P.; Redmond, W.J.; Rainville, P.; Marchand, S. Descending Analgesia–When the Spine Echoes What the Brain Expects.
Pain 2007, 130, 137–143. [CrossRef] [PubMed]
46. Jensen, M.P. A Neuropsychological Model of Pain: Research and Clinical Implications. J. Pain 2010, 11, 2–12. [CrossRef] [PubMed]
47. Salomons, T.V.; Johnstone, T.; Backonja, M.-M.; Shackman, A.J.; Davidson, R.J. Individual Differences in the Effects of Perceived
Controllability on Pain Perception: Critical Role of the Prefrontal Cortex. J. Cogn. Neurosci. 2007, 19, 993–1003. [CrossRef]
[PubMed]
48. Marcuzzi, A.; Chakiath, R.J.; Siddall, P.J.; Kellow, J.E.; Hush, J.M.; Jones, M.P.; Costa, D.S.J.; Wrigley, P.J. Conditioned Pain
Modulation (CPM) Is Reduced in Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of CPM and the Role of
Psychological Factors. J. Clin. Gastroenterol. 2019, 53, 399–408. [CrossRef] [PubMed]
49. Nahman-Averbuch, H.; Nir, R.R.; Sprecher, E.; Yarnitsky, D. Psychological Factors and Conditioned Pain Modulation: A
Meta-Analysis. Clin. J. Pain 2016, 32, 541–554. [CrossRef] [PubMed]
50. Paul-Savoie, E.; Marchand, S.; Morin, M.; Bourgault, P.; Brissette, N.; Rattanavong, V.; Cloutier, C.; Bissonnette, A.; Potvin, S. Is
the Deficit in Pain Inhibition in Fibromyalgia Influenced by Sleep Impairments? Open Rheumatol. J. 2012, 6, 296–302. [CrossRef]
[PubMed]
51. Henao-Pérez, M.; López-Medina, D.C.; Arboleda, A.; Bedoya Monsalve, S.; Zea, J.A. Patients With Fibromyalgia, Depression,
and/or Anxiety and Sex Differences. Am. J. Men’s Health 2022, 16, 155798832211103. [CrossRef] [PubMed]
52. López-Gómez, I.; Velasco, L.; Gutiérrez, L.; Écija, C.; Catalá, P.; Peñacoba, C. Symptoms in Women with Fibromyalgia after
Performing Physical Activity: The Role of Pain Catastrophizing and Disease Impact. Clin. Rheumatol. 2023, 42, 225–232. [CrossRef]
[PubMed]
53. Riquelme-Aguado, V.; Gil-Crujera, A.; Fernández-Carnero, J.; Cuenca-Martínez, F.; Gómez Esquer, F. Limb Laterality Discrimi-
nation, Evoked Sensations and Somatosensory Behavior in Fibromyalgia Syndrome: A Cross-Sectional Study. Appl. Sci. 2022,
12, 7495. [CrossRef]
54. Riquelme-Aguado, V.; Gil-Crujera, A.; Fernández-Carnero, J.; Cuenca-Martínez, F.; Klett, G.B.; Esquer, F.G. The Influence of
Emotional and Cognitive Factors on Limb Laterality Discrimination in Women with Fibromyalgia Syndrome: A Cross-Sectional
Study Secondary Analysis. Appl. Sci. 2023, 13, 1894. [CrossRef]

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.

You might also like