Mentalization deficit in bipolar patients during an acute depressive and manic episode: association with cognitive functions
Bodnar and Rybakowski Int J Bipolar Disord
Mentalization deficit in bipolar patients during an acute depressive and manic episode: association with cognitive functions
Anna Bodnar 0
Janusz K. Rybakowski 0
0 Department of Adult Psychiatry, Poznan University of Medical Sciences , ul.Szpitalna 27/33, 60-572 Poznan , Poland
Background: A number of studies in bipolar patients have shown a deficit in mentalization (theory of mind), one of the main aspects of social cognition. The aim of current study was to assess both cognitive and affective mentalization in well-defined groups of depressed and manic bipolar patients, compared to healthy control subjects, using a battery of tests measuring mentalization processes. The second aim was to investigate a possible relationship between cognitive and affective mentalization and cognitive functions in bipolar patients during a depressive and manic episode. Methods: The study involved 25 bipolar disorder type I patients (10 male, 15 female) during a depressive episode (mean 24 ± 2 points in the 17-item Hamilton Depression Rating Scale) and 25 patients (10 male, 15 female) during a manic episode (mean 27 ± 4 points in the Young Mania Rating Scale). The control group consisted of 25 healthy subjects (10 male, 15 female) without psychiatric disorders. To measure mentalization, a revised version of the Reading the Mind in the Eyes (R-MET), the Strange Stories (SS), the Faux Pas Recognition (FPR), and the Moving Shapes Paradigm (MSP) tests were used. Assessment of cognitive functioning was made using the Digit Span, Trail Making, and Wisconsin Card Sorting Tests. Results: In bipolar patients significant deficits in both cognitive and affective mentalization were demonstrated during both acute depressive and manic episodes. The impairment in FPR in manic patients was more severe than that in the depressive ones. On the other hand, in MSP, manic patients showed significantly increased intentionality for nonmentalization animations, compared with depressive patients and for “cause and effect” animations compared with control subjects. A significant relationship was found between the decrease in cognitive and affective mentalization and deficits of cognitive functions during both the depressive and manic episodes. Conclusions: The results obtained confirm the deficits of mentalization in bipolar I patients, during both acute depressive and manic episodes. We found that in such patients mentalization deficits significantly correlated with cognitive dysfunctions more so during depressive episodes.
Bipolar disorder; Mentalization; Theory of mind; Cognitive mentalization; Affective mentalization; Bipolar depression; Mania; Cognitive functions
The ability to mentalize (mentalization, theory of mind—
ToM) about other people’s mental and emotional states
forms one of the main aspects of social cognition. This
term was introduced by
Premack and Woodruff (1978)
on the basis of their study of chimpanzees, as an ability
to explain the activities and behaviors observed in other
individuals by referring to their mental status. The past
two decades of mentalization studies in humans have
lead to a proposal that mentalization contains both
cognitive and affective elements
(Shamay-Tsoory et al.
. Cognitive mentalization is an inference about the
cognitive mental state, mainly beliefs, of other persons.
Affective mentalization is an inference about the
emotional state of other persons. Distinguishing cognitive
and affective mentalization has also been proposed on
the basis of studies which demonstrated different neural
correlates of these two domains. Hynes et al. (2006), in
a functional magnetic resonance study, showed that the
medial orbitofrontal lobe, defined as Brodmann’s areas 11
and 25, was preferentially involved in affective
mentalization. This corresponded with Shamay-Tsoory et al. (2006)
study showing an impairment of affective mentalizations
in subjects having lesions in the ventromedial
prefrontal cortex. On the other hand,
Kalbe et al. (2010
a repetitive transcranial magnetic stimulation (rTMS)
approach, indicated the right dorsolateral prefrontal
cortex (DLPFC) as the brain structure mostly connected
with cognitive mentalization.
Previous research has suggested that impaired
mentalization (ToM) forms the core handicap in autism
subjects (Happé 1994). Also, two decades ago, a
deficit in mentalization was demonstrated in schizophrenia
(Frith and Corcoran 1996)
and, in subsequent studies,
it has been confirmed as an essential feature of this
(Green et al. 2015)
. The first study on mentalization
in bipolar disorder (BD) was performed by
Kerr et al.
). This involved 20 patients during a manic episode,
15 in a depressive episode, 13 in remission, and 15
control subjects and used a method of six short stories. They
found deficits in mentalization during manic and
depressive episodes where the mean intensity of mania was 13
points, according to the Bech Mania Rating Scale, and 16
points for depression, according to the Beck Depression
Inventory. In subsequent research, using tests of higher
levels of complexity, the authors demonstrated that such
deficits in BD also occur during remission periods
et al. 2004; Bora et al. 2005)
Montag et al. (2010
demonstrated that bipolar patients scored significantly lower
than control subjects for the cognitive aspect of ToM
but not for the affective one. In recent meta-analyses of
this topic, a deficit in ToM in bipolar patients in both
acute episodes and during the euthymic state has been
(Samamé et al. 2015; Bora et al. 2016)
However, lately, Haag et al. (2016) did not show differences in
visual theory of mind abilities between euthymic bipolar
patients and healthy controls.
In some mentalization research studies, a concomitant
assessment of cognitive functions has been performed. In
a few, a possible relationship between mentalization and
cognitive functions has been suggested. In the study of
Bora et al. (2005), BD patients displayed an impairment in
many cognitive tasks, including those related to sustained
attention. Lahera et al. (2008) showed impaired sustained
attention and executive functions in such patients. In the
study of Ioannidi et al. (2015) BD patients had poorer
performances in verbal memory and visuospatial
working memory during both the acute and euthymic phases
of the illness. Impaired immediate memory and
executive functions were only noted during episodes of illness.
Olley et al. (2005) showed an impaired performance on
the Stroop task in remitted BD patients and a correlation
between ToM and the CANTAB Stocking of Cambridge
task. However, Wiener et al. (2011) while finding
significant impairments on the subtests of CANTAB battery
in BD patients, did not find a relationship between these
tests and mentalization results. Recently, Van Rheenen
et al. (2014) showed a significant correlation between
tests measuring social cognition and neurocognition but
not between neurocognition and emotional regulation.
It is thus conceivable that mentalization
abnormalities could be connected with manic and/or depressive
symptoms of BD. Therefore, in this study, an attempt
was made to assess both cognitive and affective
mentalization in well-defined groups of manic and depressed
bipolar patients, compared to healthy control subjects,
using a battery of tests measuring mentalization
processes. We also hypothesized that, during an acute manic
and depressive episode such abnormalities can be
connected with cognitive functions. Therefore, the second
aim of the study was to investigate a possible relationship
between cognitive and affective mentalization and
cognitive functions in these groups of bipolar patients and
The study was performed on 50 patients with
bipolar mood disorder type I (20 male, 30 female) aged
19–65 years, with a duration of illness of 11 ± 10 years.
They were hospitalized in the inpatient clinic of the
Department of Adult Psychiatry, Poznan University
of Medical Sciences, on account of an acute manic or
depressive episode of BD. A consensus diagnosis of BD
was made for each patient by at least two psychiatrists
according to DSM-IV criteria (SCID)
(First et al. 1996)
Exclusion criteria covered any other psychiatric
co-morbidity or serious medical condition.
Twenty-five patients (10 male, 15 female), aged
41 ± 14 years, were studied during a depressive episode,
and 25 patients (10 male, 15 female) aged 35 ± 14 years
during an acute manic episode. The criterion for
inclusion in the study for depressive patients was an
intensity of depression, as assessed by the 17-item Hamilton
Depression Rating Scale (HDRS)
≥ 18 points and for manic patients an intensity of mania,
as assessed by the Young Mania Rating Scale (YMRS)
(Young et al. 1978)
—of ≥ 20 points.
On the day of study, the patients received
pharmacological treatment: antidepressant and/or
mood-stabilizing drugs in depression and antipsychotic and/or
mood-stabilizing drugs in mania. The number of patients
(in parentheses), taking individual drugs was as follows:
lithium (23), olanzapine (20), valproate (20), quetiapine
(16), venlafaxine (10), haloperidol (8), paroxetine (8),
lamotrigine (5), aripiprazole (4), risperidone (4),
carbamazepine (4), topiramate (2), bupropion (1), escitalopram
(1), mirtazapine (1).
A comparison group consisted of ten healthy men and
15 healthy women, aged 36 ± 11 years who had
volunteered to be studied in response to an internet
advertisement. They did not report any psychiatric disturbance in
themselves or in any 1st degree members of their family.
The number of years of education was 13 ± 3 years in
depressed patients, in manic patients 15 ± 3 years, and in
control subjects 16 ± 2 years.
Assessment of mentalization
A revised version of the Reading the Mind in the Eyes
Test, the Strange Stories Test, the Faux Pas Recognition
Test, and the Moving Shapes Paradigm were used for the
measurement of mentalization. Previously, these scales
had been translated into Polish by three independent
translators, then, the best version was selected and
backtranslation performed. The reliability of the tests was
assessed by the Cronbach’s alpha factor.
The Reading Mind in Eyes Test (R‑MET)
The revised version of the R-MET consists of 36
photos presenting the eyes and their adjacent areas. All the
pictures show exactly the same region of the face—from
the middle of the nose to the area above the brows. The
subject being studied is asked to choose one of the four
terms which best describes what the person on the
picture is thinking or feeling. This test assesses the
ability to identify both cognitive and affective mental states
because, for inferring what the person on the picture is
thinking or feeling it includes, among others, such terms
as suspicious (cognitive component) and fearful (affective
Baron-Cohen et al. (2001
Strange Stories (SS)
This tool was introduced by
and it assesses
the ability to understand a lie, a white lie, a figurative
expression, irony, or persuasion. After presentation of
each story, the subject is asked to answer a question
connected with its content. A correct answer requires an
inference about the mental state of the character in the
story. In this study, five stories for assessing cognitive
mentalization, as well as five control stories requiring
inferences about physical causality are used.
The Faux Pas Recognition Test (FPR)
This test was introduced by
Stone et al. (1998
definition, a faux pas occurs when someone says something
without thinking that the person who hears it may not
wish to hear it or be offended or hurt by it. The test used
in this study consists of ten stories arranged in random
order—five stories with social condition mistakes and five
control stories. The subject being studied is asked to read
the story and answer a few questions connected with it.
In the understanding and recognition of the Faux Pas,
both cognitive and affective mentalizations are involved.
Moving Shapes Paradigm (MSP)
This is a collection of 12 computer animations designed
Abell et al. (2000
). Each lasts 34–35 s and presents
two moving triangles: one large red and one small blue.
In this study three groups of four animations each, were
used: (1) random animations: triangles moving about
aimlessly without interactions; (2) cause-and-effect
animations: the triangles are interacting: following, fighting,
dancing, etc.; (3) mentalization animations: the triangles
are mutually reacting to each other’s mental states (e.g.,
1 triangle is trying to seduce, to ridicule, or to scare the
other). The subject studied is asked to view the
animations which are presented in a pseudo-random sequence
and answer a question: What happened during the
animation? Two criteria are assessed: appropriateness of the
attribution and the correctness of the intentionality of
the story (random, cause-and-effect, mentalization).
Assessment of cognitive functioning
Assessment of cognitive functioning was made using The
Digit Span, Trail Making and Wisconsin Card Sorting
Digit Span Test (DST)
This test is one of the subtests of the Wechsler Adult
Intelligence Scale-Revised. The first part consists of
remembering and presenting a series of digits in the
correct order, and measures short-term auditory memory.
The second part consists of remembering and presenting
a series of digits in the reverse of the order presented, and
measures verbal working memory.
Trail Making Test (TMT)
The Polish version of the Trail Making Test (TMT) is
an element of the Halstead–Reitan Test battery
. Part A of the test consists of connecting, by a
continuous line, the points between 1 and 25 as quickly as
possible and measures psychomotor speed and visual–
motor coordination. Part B consists of connecting, by a
continuous line as quickly as possible, the digits
alternatively with consecutive letters i.e., 1 – A – 2 – B − 3 – C,
etc., and reflects the ability to shift strategy and assess
executive function and visuospatial working memory.
The results, separately for A and B, are presented as the
duration of performance (in seconds), and the number of
Wisconsin Card Sorting Test (WCST)
The Wisconsin Card Sorting Test (WCST) assesses the
executive functions, controlling cognitive processes and
the strategy of solving problems. It is also a tool for the
assessment of working memory, abstract thinking, and
“set shifting,” i.e., the ability to display flexibility in the
face of changing schedules of reinforcement. The
subject is asked to match the 64 cards, according to color,
shape, and number of elements. He/she is not told how
to match. However, the subject is informed whether a
particular match is right or wrong. After ten correct
matches, the criterion is changed without informing the
participant. The test is terminated when six categories
are correctly arranged or all the cards are used.
Percentages of errors, of perseverative responses, of conceptual
responses, and the number of completed categories are
calculated. A computer version of the WCST
was used in this study.
The experimental procedure consisted of two parts, over
2 days, each lasting about 1 h, performed by one of the
authors (AB). On the first day, mentalization tests were
performed. On the second day, empathy and cognitive
functions were assessed. At the time of study, clinical
assessment by the HDRS or YMRS scale in the patient
was performed by a psychiatrist who was taking care of
the patient in the ward.
The one-way analysis of variance (ANOVA) with
Tukey’s post hoc test was performed. The belongingness to
the three groups: depressed, manic, and control subjects
made the independent variable. The dependent variables
included selected components of mentalization and
cognitive functions as well as clinical factors. The r-Pearson
Test was used to determine any correlation between the
variables. The calculations were done using the IBM
SPSS 21.0. The level of statistical significance was
determined at p < 0.05.
As calculated by the analysis of variance, the three
groups studied did not show differences due to age:
F(2,72) = 1.37; p = 0.26. They did, however, differ as to
years of education: F(2,72) = 7.96; p = 0.001. The
control group had higher levels of education compared to
the depressed group (p < 0.01) but not compared to the
manic group: (p = 0.32). The patients with depression
had marginally lower levels of education compared to the
manic ones (p = 0.06).
On the day of study, the mean intensity of depression
in the depressive patients, as measured with HDRS,
was 24 ± 2 points and the mean intensity of mania in
the manic patients, as measured by YMRS, was 27 ± 4
For mentalization measures, assessed in the whole
sample, the internal consistency coefficients were good,
with a Cronbach’s alpha for the Reading the Mind in
the Eyes: total 0.72, affective 0.52, cognitive 0.63; for the
Strange Stories: total 0.83, control stories 0.70,
mentalization stories 0.77, for the Faux Pas Recognition: total 0.91,
affective 0.68, cognitive 0.86; and for the Moving Shapes
Paradigm Tests: appropriateness 0.70, intentionality 0.52.
The results of the Reading the Mind in the Eyes,
Strange Stories, and Faux Pas Recognition Test are
presented in Table 1.
There were significant differences between groups in
the Reading the Mind in the Eyes Test. Post hoc
comparisons revealed a deficit in mentalization, both cognitive
and affective, measured by this test, in both the
depressive and manic patients, compared to healthy subjects.
This was also the case for the Strange Stories Test, where
both depressive and manic patients obtained significantly
worse results than the control subjects, for both
mentalization and control stories.
Likewise, there were significant differences between
groups in the Faux Pas Recognition Test. Post hoc
comparisons revealed a significant reduction in ability for such
recognition in both depressive and manic patients,
compared to healthy subjects. Furthermore, manic patients
scored worse in this test, compared to the depressive
ones. Such an impairment applied to both cognitive and
affective mentalization in both groups of bipolar patients,
and the manic patients had greater deficits in affective
mentalization, compared to depressed ones.
All the differences above remained valid after
corrections for multiple testing.
The results of the Moving Shapes Paradigm are shown
in Table 2.
Significant differences between groups were also
observed for mentalization abilities as measured by the
Moving Shapes Paradigm Test. Post hoc comparisons
revealed a deficit in both cognitive and affective
mentalization, measured by this test, in both depressive and manic
patients, compared to healthy subjects. These differences
remained valid after corrections for multiple testing.
For the mentalization and random animations both
depressed and manic patients scored lower than the
control subjects, while, in “cause and effect” animations, this
was only the case for manic patients. Both groups were
impaired in affective mentalization and on
appropriateness for the total, mentalization and random animations.
These differences remained valid after corrections for
However, for appropriateness of “cause and effect”
animations, this was only observed in manic patients
(not valid after multiple testing). For intentionality, both
groups showed an impaired score in mentalization
animation (valid after multiple testing) and increased scores
in random animations (valid after multiple testing only
for mania). For intentionality, total and “cause and effect,”
manic patients scored higher than those depressed (valid
after multiple testing only for “cause and effect”) and, in
“cause and effect” animations higher than the control
subjects (not valid after multiple testing).
For each of the four mentalization tests the differences
between groups did not change when the results were
controlled for the years of education.
The results of all the cognitive tests (Digit Span Test,
TMT A, TMT B, WCST: percentage of errors,
percentage of perseverative responses, completed categories,
percentage of conceptual responses) were lower in both
manic and depressive patients compared to healthy
subjects while no difference between depressive and manic
patients was found. To assess any possible relationship
between mentalization measures and cognitive
function tests, a correlation analysis of the results obtained in
depressive and manic episodes was performed and is
presented in Tables 3 and 4.
An analysis of a relationship between mentalization
and cognitive function tests during depression did not
find any correlations between mentalization and the
Digit Span Test. On the other hand, 32 correlations were
obtained between the four mentalization tests and the
results of the TMT and WCST. A higher level of general
mentalization was associated with better cognitive
planning and efficiency of thinking, as well as with a fewer
number of errors and perseverative responses in WCST.
A better performance on the Faux Pas Recognition Test
was connected with psychomotor speed, visual
perception, visual–spatial coordination, and working memory.
A higher level of cognitive mentalization was associated
with better cognitive planning and efficiency of thinking
(except for FPR), with a fewer number of errors and
perseverative responses in WCST (R-MET and SS) and with
psychomotor speed, visual perception, and visual–spatial
coordination, and working memory (MSP). A higher level
of affective mentalization was associated with a fewer
number of errors and a higher percentage of conceptual
responses in WCST (R-MET, FPR).
As in depression, the analysis of a relationship between
mentalization and cognitive function tests during mania
did not find any correlations between mentalization and
the Digit Span Test. Fifteen correlations were obtained
between the four mentalization tests and the results of
the TMT and WCST. A higher level of general
mentalization was associated with better cognitive planning.
Better performance on the Faux Pas Recognition Test was
connected with efficiency of thinking and fewer errors on
WCST. A higher level of cognitive mentalization assessed
by MSP was associated with better psychomotor speed
and visual–spatial coordination and, when assessed by
the R-MET test, with better attention and visual–spatial
working memory. A higher level of affective
mentalization was associated with better cognitive planning, a
fewer number of perseverative responses (R-MET),
better efficacy of thinking (FPR), and better psychomotor
speed and visual–motor coordination.
In both tables no correlation coefficient was 0.64 or
higher which would be necessary to withstand correction
for multiple testing.
The first finding of our study is the demonstration of
deficits in mentalization (theory of mind) in bipolar patients,
during both acute manic and depressive episodes. In our
study, this was evidenced by the use of a number of tests
for measuring mentalization These included the
Reading the Mind in the Eyes, the Strange Stories, the Faux
Pas Recognition Tests, and the Moving Shapes Paradigm
Tests. The results obtained indicate an impairment of
both cognitive and affective mentalization in the groups
of bipolar patients studied. This corresponds to the
results of recent meta-analyses
(Samamé et al. 2015; Bora
et al. 2016)
Further analysis of our mentalization results showed
that there were some differences in this respect between
depressive and manic patients. In the Faux Pas
Recognition Test the impairments in manic patients were more
severe than in the depressive ones in both the total as
well as cognitive and affective scores. On the other hand,
in the Moving Shapes Paradigm Test, manic patients
showed significantly increased intentionality for
nonmentalization animations, compared to depressive
patients and, for “cause and effect” animations,
compared to the control subjects. This may be connected
with the fact that manic patients perceive social stimuli
from strangers as more positive and directed at them
and not as random behavior
(Piff et al. 2012)
perception of intentionality in manic patients could also
correspond with the increased affective empathy
(overempathising) we reported in bipolar patients during a
(Bodnar and Rybakowski 2017)
The second finding of our study is that, in bipolar
patients during an acute episode, mentalization
deficits significantly correlated with cognitive
dysfunctions. Impaired neurocognitive functioning in BD, more
marked during an acute episode, is a well-demonstrated
(Tsitsipa and Fountoulakis 2015)
. In the
current study we found many correlations between all
the four mentalization tests applied and the results of
such neuropsychological tests as TMT and WCST which
measure psychomotor speed, visual–motor coordination,
visuospatial working memory, and executive functions.
Such correlations were more numerous in depressive
than in manic patients. This may correspond to other
studies pointing to cognitive dysfunctions in BD,
concomitant to mentalization disturbances
(Bora et al. 2005;
Lahera et al. 2008; Wiener et al. 2011; Ioannidi et al.
, as well as to a relationship between mentalization
and cognitive functions reported in such patients
et al. 2005; Van Rheenen et al. 2014)
Disturbances of mentalization, as well as their
relationship with cognitive dysfunctions during acute episodes
of BD, should be regarded in the context of brain
abnormalities in this illness. The neural circuits underlying the
pathophysiology of mood disorders mostly include the
prefrontal cortex and anatomically related limbic
(Price and Drevets 2012)
. According to
et al. (2006
) the main role is played by the anterior limbic
network comprising the ventral and orbital parts of the
prefrontal cortex, connected reciprocally with the
amygdala, parahippocampal gyrus, insula, and the anterior
part of the cingulated gyrus. As mentioned previously,
the ventral and orbital parts of the prefrontal cortex have
been suggested for affective mentalization
(Hynes et al.
2006; Shamay-Tsoory et al. 2006)
while Kalbe et al. (2010)
suggests that the brain structure mostly associated with
cognitive mentalization is the right dorsolateral
prefrontal cortex (DLPFC). However, a recent study of
Yeh et al.
) did not find differences between groups of patients
having DLPFC vs ventromedial prefrontal cortex damage
to both cognitive and affective aspects of mentalization.
In our study we obtained significant correlations between
the results of the four tests measuring mentalization
studies, and such cognitive function tests as the TMT and
WCST. A meta-analysis of structural neuroimaging
studies showed that the performance on these tests is related to
the volume of the prefrontal cortex, mainly the lateral and
medial parts of it
(Yuan and Raz 2014)
. Recent studies have
also shown an association between the dorsomedial
prefrontal cortex and TMT B performance
(Miskin et al. 2016)
and between DLPFC and WCST
(Boschin et al. 2016)
may indicate that a DLPFC abnormality in bipolar patients
plays a role for both mentalization deficits and cognitive
disorders. Such an abnormality and the resulting
disturbances are less intense in BD patients than in schizophrenia
(Bora and Pantelis 2016)
as was confirmed in our study on
WCST performance (Rybakowski et al. 2006).
Although the discussion above mainly concerned the
prefrontal cortex it should be indicated that other areas
of the brain may be also important for mentalization
processes. According to a meta-analysis of
et al. (2016
), besides the prefrontal cortex, the second
most important brain structure for mentalization is the
temporoparietal junction. However, there is no data on
the involvement of the temporoparietal junction in such
cognitive tests as TMT and WCST.
Based on the differences obtained between manic and
depressive patients, and especially for an increased
intentionality for random and “cause and effect” animations in
manic patients, it can be speculated that these are
connected with differences in functional brain activities in
these episodes. An example of this can be the right
amygdala–hippocampal connectivity, increased in mania and
decreased in depression
(Li et al. 2015)
The limitation of our study is that the bipolar patients
were actively treated during the study, receiving
antidepressant and/or mood-normalizing drugs in
depression and antipsychotic and/or mood-normalizing drugs
in mania. Another limitation may be a difference in the
mean education level between the bipolar depressive
patients and the control group. On the other hand, the
strength of our study is the use of four test for measuring
mentalization and the well-designed groups of
depressive and manic patients. Therefore, bearing these
limitations in mind, we believe that our results strongly suggest
that mentalization is significantly impaired during acute
episodes of BD disorder although there may be some
differences between depressive and manic episodes. Such
impairments significantly correlate with the results of
neuropsychological tests such as TMT and WCST.
BD: bipolar disorder; DLPFC: dorsolateral prefrontal cortex; DST: Digit Span Test;
FPR: Faux Pas Recognition Test; HDRS: Hamilton Depression Rating Scale; MSP:
Moving Shapes Paradigm; R-MET: Reading the Mind in the Eyes Test; rTMS:
repetitive transcranial magnetic stimulation; SS: Strange Stories; ToM: theory of
mind; WCST: Wisconsin Card Sorting Test; YMRS: Young Mania Rating Scale.
AB designed the study, conducted the literature search, performed
mentalization assessment, made statistical analysis, and wrote the first draft of the
paper. JKR designed the study, recruited the patients, took part in the
elaboration of results, and wrote the final version of the manuscript. Both authors
read and approved the final manuscript.
The authors declare that they have no competing interests.
Availability of data and materials
All datasets for this manuscript, in Excel format, are available on request from
the first author .
Ethics approval and consent to participate
The study was approved by the Bioethics Committee of Poznan University of
Medical Sciences, and all the participants gave their written informed consent,
after the nature of the procedures had been fully explained to them.
Consent for publication
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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