Identification of the Features of Emotional Dysfunction in Female Individuals With Methamphetamine Use Disorder Measured by Musical Stimuli Modulated Startle Reflex

Abstract

Emotional dysregulation contributes to the development of substance use disorders (SUDs) and is highly associated with drug abuse and relapse. Music as a contextual auditory stimulus can effectively stimulate the reward circuitry, modulate memory associated with drug taking, and enhance emotional experiences during drug taking. However, the studies of the emotional responses to music in individuals with SUDs are scarce. Using startle reflex and self-reports, this study assessed the psychophysiological and cognitive emotional responses (i.e., valence, arousal and proximity) to happy, peaceful, and fearful music stimuli in 30 females with methamphetamine use disorder (MUD) and 30 healthy females. The results found that participants with MUD showed an inhibited startle response to fearful music compared to normal controls (t = 3.7, p < 0.01), and no significant differences were found in the startle responses to happy and peaceful music between the two groups. For the self-reported ratings, participants with MUD showed a decreased arousal in the response to fearful (t = 4.1, p < 0.01) and happy music (t = 3.8, p < 0.01), an increased valence in the response to fearful music (t = 4.4, p < 0.01), and a higher level of proximity in the response to fearful (t = 3.8, p < 0.01) and happy music (t = 2.2, p = 0.03). No significant differences were found in the rating of arousal to peaceful music, the valence to happy and peaceful music, as well as the proximity to peaceful music between the two groups. The females with MUD showed attenuated psychophysiological response and potentiated cognitive response (i.e., valence, arousal) to fearful music, as well as a high proximity to musical stimuli with high arousal regardless of its valence. These results have important implications for promoting the effectiveness of assessment and therapy selections for female MUD patients with impaired emotion regulation.

Full text

ORIGINAL RESEARCH
published: 05 June 2018
doi: 10.3389/fnhum.2018.00230
Identification of the Features of
Emotional Dysfunction in Female
Individuals With Methamphetamine
Use Disorder Measured by Musical
Stimuli Modulated Startle Reflex
Xi-Jing Chen1,2,Chun-Guang Wang 3,Wang Liu 1,2,Monika Gorowska 2,Dong-Mei
Wang1,2* and Yong-Hui Li1,2
1CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China, 2Department of Psychology, University of
Chinese Academy of Sciences, Beijing, China, 3Beijing Municipal Bureau of Drug Rehabilitation Administration, Beijing, China
Edited by:
Xiaochu Zhang,
University of Science and Technology
of China, China
Reviewed by:
Lingdan Wu,
Universität Konstanz, Germany
Annie Lynne Heiderscheit,
Augsburg College, United States
*Correspondence:
Dong-Mei Wang
wangdm@psych.ac.cn
Received: 28 February 2018
Accepted: 18 May 2018
Published: 05 June 2018
Citation:
Chen X-J, Wang C-G, Liu W,
Gorowska M, Wang D-M and Li Y-H
(2018) Identification of the Features
of Emotional Dysfunction in Female
Individuals With Methamphetamine
Use Disorder Measured by Musical
Stimuli Modulated Startle Reflex.
Front. Hum. Neurosci. 12:230.
doi: 10.3389/fnhum.2018.00230
Emotional dysregulation contributes to the development of substance use disorders
(SUDs) and is highly associated with drug abuse and relapse. Music as a contextual
auditory stimulus can effectively stimulate the reward circuitry, modulate memory
associated with drug taking, and enhance emotional experiences during drug taking.
However, the studies of the emotional responses to music in individuals with SUDs are
scarce. Using startle reflex and self-reports, this study assessed the psychophysiological
and cognitive emotional responses (i.e., valence, arousal and proximity) to happy,
peaceful, and fearful music stimuli in 30 females with methamphetamine use disorder
(MUD) and 30 healthy females. The results found that participants with MUD showed
an inhibited startle response to fearful music compared to normal controls (t= 3.7,
p<0.01), and no significant differences were found in the startle responses to happy
and peaceful music between the two groups. For the self-reported ratings, participants
with MUD showed a decreased arousal in the response to fearful (t= 4.1, p<0.01) and
happy music (t= 3.8, p<0.01), an increased valence in the response to fearful music
(t= 4.4, p<0.01), and a higher level of proximity in the response to fearful (t= 3.8,
p<0.01) and happy music (t= 2.2, p= 0.03). No significant differences were found
in the rating of arousal to peaceful music, the valence to happy and peaceful music, as
well as the proximity to peaceful music between the two groups. The females with MUD
showed attenuated psychophysiological response and potentiated cognitive response
(i.e., valence, arousal) to fearful music, as well as a high proximity to musical stimuli
with high arousal regardless of its valence. These results have important implications
for promoting the effectiveness of assessment and therapy selections for female MUD
patients with impaired emotion regulation.
Keywords: substance use disorders, methamphetamine, music stimuli, startle reflex, females
Abbreviations: MUD, methamphetamine use disorder; SUDs, substance use disorders.
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Chen et al. Emotional Dysfunction in Methamphetamine Use Disorder
INTRODUCTION
Substance use disorders (SUDs) is featured as ‘‘a cluster of
cognitive, behavioral and physiological symptoms indicating
that the individual continues using the substance despite
significant substance-related problems’’ in Diagnostic and
Statistical Manual of Mental Disorders Fifth Edition ([DSM-
5], p. 483, American Psychiatric Association, 2013). Emotional
dysregulation is an important problem that contributes to
the development of SUDs (London et al., 2004, 2015).
Chronic drug abuse involves the plastic change in the neural
circuits mediating the reward system and anti-reward system
(Koob and Moal, 2005). With the prolongation of drug
use, the reward system increases its threshold (i.e., decrease
neurotransmitter function) as a neuroadaptive change to
make abusers become more difficult to experience pleasure
feelings, and the anti-reward system including corticotrophin-
releasing factor, norepinephrine and dynorphin are activated
to produce negative or stress states. Consequently, depression
and anxiety become the two most prevalent negative emotions
in methamphetamine abusers (London et al., 2004). Moreover,
research found the hypoactivation of the ventromedial prefrontal
cortex/anterior cingulate cortex (vmPFC/rACC) and abnormal
(i.e., no activation, hypoactivation, or hyperactivation) activation
of amygdala and insula in individuals with SUDs (Salloum et al.,
2007; Gilman and Hommer, 2008; O’Daly et al., 2012; Wilcox
et al., 2016). These findings indicate the dysfunctional emotion
regulation in people with SUDs, including dampened cognitive
function for inhibiting intense affect, and abnormal emotion
processing and reactivity.
Emotional reactivity has been commonly applied as one
dimension for assessing the impairment of emotional regulation
in people with SUDs (Blanchart et al., 2008; Smoski et al.,
2011; Savvas et al., 2012). Previous studies that utilized visual
emotional stimuli (i.e., pictures, facial expressions, videos) for
eliciting emotional responses found inconsistent findings across
the different types of drug users. Stimulant substance users
(e.g., cocaine) demonstrated a more sensitive perception to the
pleasant to unpleasant stimuli, and depressant users (e.g., heroin)
tended to neutralize the rating on both unpleasant and pleasant
stimuli (Kornreich et al., 2003; Aguilar de Arcos et al., 2005).
These results suggest that there are different characteristics of
emotional experience across drug types depending on the various
clinical impact of drugs. In addition, research found the gender
differences in emotion regulation between female and male
with SUDs (Potenza et al., 2012). Compared to male cocaine
dependents, female dependents showed an increased activation
in amygdala and insula during a personalized stressful narrative,
indicating that female with SUDs may be more vulnerable and
experience more emotion regulation difficulties when facing
stress. These findings suggest that gender should be taken into
consideration in the assessment and therapy selection for treating
people with SUDs.
The emotional reactivity can be measured using self-reports
and psychophysiological measurements. The self-reported
valence, arousal and proximity of emotions assess the cognitive
aspect of emotion regulation (i.e., emotion recognition,
perception). Valence refers to the nature of the emotional
stimulus (i.e., positive vs. negative, or pleasurable vs. unpleasant);
arousal refers to the intensity of the stimulus (i.e., low or
high intensity); and proximity refers to the motivational
reaction toward the emotional stimulus (i.e., approach or
avoidance). Valence and arousal reflect the nature and intensity
of motivational activation respectively (Bradley et al., 2001). The
research found that individuals with SUDs reported high arousal
(i.e., increase of anxiety, heart rate and salivary cortisol levels),
negative valence (increased negative emotion), and avoidance
motivation in the response to stressful stimuli, which often lead
to drug craving and abuse (Sinha et al., 2000; Baker et al., 2004).
Psychophysiological measurements mainly focus on assessing
the implicit physiological responses to emotions with or without
consciousness. Startle reflex is an effective measure that has been
extensively used for probing emotional reactivity (Lang et al.,
1990; Cook et al., 1992). As a response of the defensive emotional
system, it can record the automatic defensive reaction (i.e., the
amplitude of the eye link) in response to a loud white noise.
The startle reflex is enhanced in response to negative emotional
stimuli and is inhibited in response to positive emotional stimuli
in normal people (Lang et al., 1998; Bradley and Lang, 2000).
Music as auditory stimuli can effectively modulate emotional
experience. Music reward involves the brain regions that highly
overlap with the regions of drug reward (Salimpoor et al., 2011;
Zatorre and Salimpoor, 2013). A fMRI study (Menon and Levitin,
2005) found that music mediated the activity of mesolimbic
reward circuitry including nucleus accumbens (NAcc), ventral
tegmental area (VTA), hypothalamus and insula. Pleasant music
significantly activated the interaction between the NAcc and
hypothalamus, as well as insula and orbitofrontal cortex (Blum
et al., 2010). The quality of musical elements (e.g., rhythm,
harmony, timbre, musical structure, speed, power and melody) is
associated with the valence and arousal of emotional experiences
(Zhou, 1999). It is important to note the distinct characteristics
of music as an emotional stimulus comparing to other kinds
of emotional stimuli (e.g., picture, video, script). For example,
people normally withdraw or avoid from the negative emotional
stimuli, yet some listeners have an approach motivation toward
sad music that match their affect state for improving mood
(Garrido and Schubert, 2013).
Moreover, musical experience and training can change
the plasticity of brain regions related to emotion regulation.
Musicians and people with musical training exhibited a higher
level of musical rewarding experience than people with no
musical background (Mas-Herrero et al., 2013). A EEG study
revealed that after 3 months of improvisational music therapy
for depressed clients, significant increased absolute power was
found at left fronto-temporal alpha and theta, indicating the
impact of music intervention on reducing depression and anxiety
symptoms (Fachner et al., 2013). Gender effect was found when
use music for emotion regulation. The activation of medial
prefrontal cortex (mPFC) decreases in males and increases in
females during music listening (Carlson et al., 2015).
In the context of SUDs, animal study demonstrated that
after repeatedly associated with methamphetamine, music as
a contextual conditioned stimulus can significantly increase
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Chen et al. Emotional Dysfunction in Methamphetamine Use Disorder
extracellular dopamine levels in the nucleus accumbens and
basolateral amygdala, as well as locomotor activity in rats
(Polston et al., 2011), suggesting that music can effectively
stimulate the dopamine circuitry and modulate associated
memory of drug taking. An investigation of 143 substance
abusers found that music was a common contextual stimulus
during drug using. Seventy percent of the substance abusers
listened to music for more than 1 h each day, and reported that
music enhanced their emotional experience during drug taking
(Dingle et al., 2015).
Despite the powerful impact of music on emotion regulation,
the studies of emotional responses to music in people with
SUDs are scarce. Given the different neurotoxicity of drugs
and gender effect, the aim of this study is to explore the
emotional perception and responses to music stimuli in females
with methamphetamine use disorder (MUD). We hypothesize
that female individuals with MUD will have a biased emotional
perception and response to pleasant and unpleasant musical
stimuli compared to normal controls.
MATERIALS AND METHODS
Participants
Thirty female participants with MUD were recruited from the
Xin-He Drug Rehabilitation Center, and 30 healthy female
participants as controls were recruited from a manufacture
factory in Beijing, China. Two psychologists interviewed
all participants for gathering demographic information and
screening, and then participants filled out the State-Trait Anxiety
Inventory, Beck Depression, and Barcelona Music Reward
Questionnaire for assessing anxiety, depression and musical
reward sensitivity.
For the MUD participants, the inclusion criteria are:
(1) aged 18–55 years; (2) a history of using methamphetamine
and fulfilled the diagnosis of stimulant use disorder in
the Chinese version of DSM-5 (pp. 232–238, American
Psychiatric Association, 2014). Stimulant use disorder refers
to the clinically significant impairment or distress caused by
the use of amphetamine-type substance, cocaine, or other
kinds of stimulant, such as amphetamine, dextroamphetamine,
methamphetamine, cocaine and methylphenidate.
Exclusion criteria: (1) a history of brain damage or a
coma over 30 min; (2) a history of using other kind of
drugs (e.g., heroin, cocaine); (3) illiteracy; (4) a history or a
family history of mental illness; and (5) hearing problems. All
participants had no musical training history. The study was
carried out in accordance with the recommendation of the
Declaration of Helsinki. The protocol was approved by the
Ethics Committee of Institute of Psychology, CAS (H17001). All
subjects gave a written informed consent in accordance with the
Declaration of Helsinki.
Musical Excerpts
Three musical excerpts presenting three emotions (i.e., happy,
fearful, peaceful) were adapted from a previous study (Vieillard
et al., 2008). Five excerpts of each emotion were selected out of a
pool of 42 excerpts based on the assessment of 30 music majored
colleague students. They evaluated the valence (0 = pleasant,
9 = unpleasant) and arousal (0 = relaxing, 9 = stimulating) of
each musical excerpt using a Likert scale. The happy excerpts
were selected based on the high arousal and valence, the fearful
excerpts were selected based on the high arousal and low valence,
and the peaceful excerpts were selected based on the low arousal
and high valence. Then the top five excerpts of each emotion were
selected for the study (see Supplementary Table S1 for the list of
the music excerpts).
Fifteen chosen music excerpts were further evaluated and
validated by 46 college students with no musical training on the
dimensions of valence, arousal and proximity (0 = approach,
9 = withdraw). In terms of valence, happy excerpts was higher
than peaceful excerpts (t= 5.6, p<0.01) and fearful excerpts
(t= 16.95, p<0.01), and peaceful excerpts was higher than
fearful excerpts (t= 12.25, p<0.01); in terms of arousal, peaceful
excerpts was lower than happy excerpts (t=−7.59, p<0.01)
and fearful excerpts (t=−5.45, p<0.01), and there was no
significant difference between happy and fearful excerpts; in
terms of proximity, fearful excerpts was lower than peaceful
excerpts (t=−16.69, p<0.01) and happy excerpts (t=−14.02,
p<0.01), and no significant difference was found between happy
and peaceful excerpts. The results indicated that the selected
music excerpts elicited differentiated emotions corresponding
with their valence, arousal, and proximity. All music excerpts
were piano melodic music produced by a digital synthesizer with
a duration from 10 s to 14 s. Each excerpt was normalized to
equate loudness using the normalization function of the Audition
3software.
Measurements
Startle Reflex
White noise of 100 dB, 50 ms burst was presented over Sony
MDR-XB500AP head-phones to elicit startle responses. Five
white noise probes were presented during the first minute with
a randomized interval before the presentation of music stimuli.
Then three types of music excerpts were presented with a 3 s
interval between each excerpt, and each type of music was
presented with three randomly placed startle probes (Figure 1).
For startle data recording, the Eye-blink Electromyographic
(EMG) data were collected from the orbicularis oculi using two
mini-electrodes placed below the left eye (Larson et al., 2005).
After each white noise, EMG activity (µv) was automatically
recorded. EMG signals pass through bandpass filtered at 10 and
500 Hz and were amplified by 1000. The sampling rate was set
at 1000 Hz. The maximum amplitude of each response between
20 ms and 120 ms after startle probe onset was considered as
valid data and included for analysis (Balaban et al., 1986). To
reduce individual variability in the raw startle reflex data, the raw
data were standardized within in each participant, In the light of
a previous study (Roy et al., 2009), the standardized score was
expressed as T scores (50 + 10 Hz), which led to a mean of 50 and
a standard deviation of 10 for each participant.
Self-Reported Emotional Responses
Self-reported emotional responses to music excerpt were
measured using a Likert scale scored from 0 to 9. After each music
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Chen et al. Emotional Dysfunction in Methamphetamine Use Disorder
FIGURE 1 | Distribution of probes during the presentation of three types of music excerpts. Note:∗White noise probe.
excerpt, the participants assess it on the dimension of valence
(0: unpleasant, 9: pleasant), arousal (0: relaxing, 9: stimulating),
and proximity (0: withdraw, 9: approach).
Anxiety
Anxiety was measured using the Chinese version of State-trait
Anxiety Inventory. It consists of 20 items and ranged from 20 to
80. Higher scores indicate higher level of anxiety.
Depression
Depression was measured using the Chinese version of Beck
Depression Inventory. It consists of 13 items and ranged from
0 to 63 (4–7: mild depression, 8–15: moderated depression, 16 or
higher: severe depression). Higher scores indicate higher level of
depression.
Musical Reward Sensitivity
Barcelona Musical Reward Questionnaire was developed
by Mas-Herrero and his colleagues (Mas-Herrero et al.,
2013) for assessing music reward sensitivity. It evaluates
the sensitivity to music from the dimensions of emotional
evocation, sensory-motor, mood regulation, musical seeking
and social reward. It consists of 20 items and scored
from 1 (completely disagree) to 5 (completely agree). A
higher score indicates a higher level of musical reward
sensitivity (0–40: low, 40–60: standard, 60 or higher:
high).
Procedure
The researcher helped the participants to put on headphones
and affix the electrodes for startle reflex. The participants sat
comfortably in a quiet room and watched natural scenes (i.e., the
sea life aquarium) on a computer screen for 1 min to relax.
Before the presentation of the music stimuli, five white noise
probes were played randomly during 1 min. Then, three types
emotional music excerpts were presented in a counterbalanced
order across subjects. The startle reflex responses were recorded
during the listening process. After each music excerpt, the
participants rated the valence, arousal and proximity of the
excerpt.
Data Analysis
Data analysis was performed using the Statistical Product and
Service Solutions (SPSS) 17.0. The comparison of demographic
information, anxiety, depression, music reward, self-reported
ratings and startle reflex between two groups were analyzed using
independent sample t-test.
RESULTS
The two groups were matched in age, anxiety, depression and
musical reward sensitivity (Table 1). The control group had
more years of education than the methamphetamine (MA)
group.
Startle Reflex
Compared to the normal control, the MA group showed
a lower level of startle response to fearful music (MA:
49.08, Control: 53.66, t= 3.7, p<0.01). There was no
significant difference in the response to peaceful and happy
music between the two groups, although the startle reflex
TABLE 1 | The comparison between the two groups in demographic information and clinical characteristics.
Methamphetamine group Control group Difference
(n= 30) (n= 30) p
Outcome M (SD) M (SD)
Age (year) 30.97 (7.41) 29.58 (7.17) 0.09
Education (year) 9.21 (3.12) 12.30 (2.14) 0.01∗∗
BMRQ 76.21 (9.08) 75.83 (7.31) 0.07
BDI 12.63 (9.69) 12.35 (9.35) 0.08
TSAI (state) 37 (10.38) 36.67 (9.56) 0.07
TSAI (trait) 39.64 (7.93) 40.21 (8.22) 0.06
Abstinent period (month) 8.68 (3.64) - -
Total time of drug use (month) 35.23 (22.41) - -
Total drug use amount in a year (gram) 82.35 (124.53) - -
Note. BMRQ, Barcelona Musical Reward Questionnaire; BDI, Beck Depression Inventory; STAI, State and Trait Anxiety Inventory; ∗∗ p≤0.01.
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Chen et al. Emotional Dysfunction in Methamphetamine Use Disorder
FIGURE 2 | Startle reflex amplitudes in response to three emotional music excerpts in the two groups. Note: MA, methamphetamine group; Control, healthy control
group; ∗∗p≤0.01.
FIGURE 3 | The self-reported emotions of arousal, valence and proximity in the two groups. Note: MA, methamphetamine group; Control, healthy control group; ∗p
≤0.05, ∗∗p≤0.01.
amplitudes to both music stimuli in the MA group were higher
(Figure 2).
Self-Reported Emotions
Compared to the control group, the MA group showed a lower
level of arousal in response to happy music (t= 3.8, p<0.01)
and fearful music (t= 4.1, p<0.01), a higher valence (i.e., more
pleasant) in response to fearful music (t= 4.4, p<0.01),
and a higher proximity (i.e., approach motive) in response to
happy (t= 2.2, p= 0.03) and fearful music (t= 3.8, p<0.01;
Figure 3).
DISCUSSION
The female participants with MUD showed an inhibited startle
response to negative (i.e., fearful) music, and a tendency of
potentiated startle response to positive music (i.e., happy,
peaceful). These reactivities that opposite to the reactions in
normal people may indicate the impaired emotional processing
and emotional regulation (Lang et al., 1998; Bradley and
Lang, 2000). Moreover, the increased self-reported valence to
fearful music, and decreased self-reported arousal of MUD
participants to both positive and negative music accords with
their dysfunctional startle reflex response, which reflects the
dampened emotional perception on the emotional valence and
arousal. These findings are in line with previous studies (Carrico
et al., 2013; May et al., 2013) that people with SUDs show
attenuated response to emotional stimuli.
The participants with MUD showed a higher level of valence
and lower level of arousal, as well as a decreased startle response
to fearful music than the normal controls suggesting their
biased emotional perception and psychophysiological reactivity
to music. Tempo and harmony influence the arousal and
valence of music emotional experience respectively (Gomez
and Danuser, 2007; Hodges, 2010). The fearful music excerpts
used in the study feature fast tempo and dissonant melodies,
which may create intense and stimulating feelings. The MUD
participants also showed a higher level of proximity to both
positive and negative music with high arousal. Given the
chronic drug use impairs the reward system, individuals with
dampened reward function may seek for the strong stimulant
feature of high arousal music to acquire pleasurable feelings.
Huron (2011) pointed out that the brain can distinguish ‘‘fake’’
negative emotions in music from real threat in life, therefore
it is ‘‘safe’’ for people to enjoy music that conveys negative
emotions. Drug abusers tend to use drugs to decrease or avoid
negative feelings (Otto et al., 2004). To be open and experience
‘‘negative’’ music and may help them to face their negative
feelings and deal with their problems instead of taking drugs.
For music therapy, music with high arousal may be used to
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Chen et al. Emotional Dysfunction in Methamphetamine Use Disorder
attract the attention and increase the motivation of patients
with SUDs.
It is noteworthy that there was no significant difference in
the cognitive responses including valence, arousal, and proximity
to peaceful music between the two groups. Given depression
and anxiety are the two most prominent negative emotions in
methamphetamine users (London et al., 2004), this result may
suggest the suitability of using peaceful music for relaxation in
treating patients with MUD as they may respond well to peaceful
music. In addition to music listening, active musical activities
such as improvisation can help people to explore and express
various feelings, facilitate meaningful communicate, gain public
recognition and bring a sense of achievement (Soshensky, 2001;
Baker et al., 2007; Silverman, 2009).
The study has several limitations. Only female subjects
with MUD participated in this study, there is a lack of the
comparison between two genders. The educations years in
participants with MUD are less than the healthy controls.
However, the music listening task did not require a high level
of cognitive function, therefore we suppose this difference did
not affect the task. The future study will add male participants,
improve the comparability of the two groups, and supply more
psychophysiological measurements, such as ERP, EEG, skin
conductance.
In summary, the study utilized emotional music stimuli to
elicit emotional responses of female individuals with MUD,
and assessed them with cognitive and psychophysiological
measurements. The results found that the females with MUD
showed inhibited psychophysiological and cognitive emotional
responses to fearful music, and a high proximity to musical
stimuli with high arousal regardless of its valence. These results
have important implications for promoting the effectiveness of
assessment and therapy for female MUD patients with impaired
emotion regulation.
DATASETS ARE AVAILABLE ON REQUEST
The raw data supporting the conclusions of this manuscript will
be made available by the authors, without undue reservation, to
any qualified researcher.
AUTHOR CONTRIBUTIONS
X-JC designed and implemented the experiment, analyzed the
data and drafted the manuscript. C-GW and WL conducted the
interview for the participants. MG helped with the data collection
process. D-MW and Y-HL guided the study design and directed
the experiment implementation.
FUNDING
This work was supported by the National Key Research
and Development Program of China (2017YFC1310405,
2016YFC0800907), the National Natural Science Foundation of
China (U1736124, 31371035), and the CAS Key Lab of Mental
Health (Y7CX424007).
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found online
at: https://www.frontiersin.org/articles/10.3389/fnhum.2018.002
30/full#supplementary-material
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Conflict of Interest Statement: The authors declare that the research was
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