4 Discussion:
The purpose of this research was to identify potential endophenotypic
markers of bipolar disorder by examining cognitive function measurements
and neurological soft signs in EBP and their unaffected FDR. This is the
first study to our knowledge that investigates NSS and neurocognitive
performance as potential combination endophenotypes for bipolar
disorder.
Except for disinhibition, all NSS scores were higher in EBP than HC in
this study. Sagheer et al. evaluated the NSS in 50 patients with bipolar
disorder and normal controls, the results indicated that patients with
bipolar disorder had higher NSS total scores, motor coordination, and
sensory integration scores than normal controls(Sagheer et al., 2018). A
2018 Meta-Analysis found that, despite the use of different instruments
to assess the NSS, the majority of studies reported that, during
episodes and remission, patients with bipolar disorder performed worse
than normal controls on motor coordination and sensory integration
items(Bora et al., 2018). The findings agree with earlier research. The
outcomes of the current investigation also matched those of a trial that
included euthymic bipolar I patients and their unaffected siblings. The
distribution of motor coordination among patients, unaffected
first-degree relatives, and healthy controls was trapezoidal, in other
words(Mrad et al., 2016). Consequently, motor coordination may be a
trait-defining characteristic of bipolar disorder.
In this study, both EBP and FDR exhibited significant cognitive
impairment, which is consistent with previous findings. Compared to HC,
EBP and FDR exhibited significant deficits in IPS, VL, and VM, whereas
there were no significant differences in RS, as measured by the
NAB-Mazes in the MCCB. The NAB-Mazes assess the reasoning and
problem-solving skills in executive function but do not target the same
areas as transfer attention shifting and response inhibition
measures(Bora et al., 2009; Burdick et al., 2011; Van Rheenen et al.,
2014). This indicates that the impairment in executive function in the
EBP may be limited to certain domains, such as WM and IPS, and not
widespread. The results of the current study are supported by a study of
cognitive functioning in unaffected first-degree relatives of bipolar
disorder, which indicated that first-degree relatives outperformed
healthy controls on the NAB-Mazes test. There were no discernible
variations in attention between first-degree relatives and controls
according to the results of the current study’s attention tests, which
were likewise consistent with the findings of this study(Calafiore et
al., 2016). The current study,
however, came to a different conclusion about social cognition than this
study. While there was no discernible difference in social cognition
between FDR and HC in their investigation, EBP and FDR both performed
worse than HC in our study. Their study employed a different sample of
FDRs who were unrelated to EBP, decreasing the impact of genetic
variables, which may be the cause of this discrepancy(Calafiore et al.,
2016). Additionally, this study’s findings on social cognition are in
line with those of a meta-analysis that examined a total of 16
investigations(Bora et al., 2016). This study found that attention was
impaired in EBP compared to HC, but there was no significant impairment
in FDR. Since there is some evidence that sustained attention deficits
in bipolar disorder may be associated with affective symptoms, this may
explain why first-degree relatives do not exhibit significant sustained
attention deficits in comparison to normal controls. Furthermore,
previous studies have found that sustained attention was not impaired in
FDR compared to the control group on a variety of measures(Kulkarni et
al., 2010; Balanza-Martinez et al., 2008; Clark et al., 2005; Kieseppa
et al., 2005).
In our study, the scores of EBP, FDR, and HC showed an upward trend in
the cognitive domains of ISP, VL, and WM, which is consistent with the
findings of previous research(Bora et al., 2009; Balanza-Martinez et
al., 2008; Bo et al., 2019). Bo et al. also discovered the following
ranking of cognitive function, from low to high: patients, followed by
first-degree relatives, and then controls. Similar cognitive deficits
were present in both EBP and FDR but to differing degrees(Lenzenweger et
al., 2013). However, only the IPS, VL, and WM cognitive domains were
found to follow this pattern in our research. This is in line with the
findings of a study of twins with bipolar I disorder, which revealed
that the patients’ siblings also showed impairments in verbal learning
and memory, indicating that these issues may be genetic(Kieseppa et al.,
2013).
Endophenotypes are internal phenotypes that exist between genes and
phenotypes(Lenzenweger et al., 2013). In recent years, numerous studies
have focused on identifying the disease’s internal phenotype from
multiple perspectives in order to investigate the pathogenesis and early
detection characteristics of bipolar disorder.48,49According to previous research, an endophenotype must meet certain
criteria, including association with disease in the population, state
independence, familial association, and co-segregation within
families(Iacono et al., 2018; Hellhammer et al., 2018). We could deduce
from our findings that ISP, VL, WM in cognitive function, and motor
coordination in NSS correspond to these endophenotype characteristics.
Both previous longitudinal and cross-sectional studies have also
suggested that ISP may be a valid endophenotype of bipolar disorder and
highly specific in distinguishing EBP and FDR from HC(Luperdi et al.,
2021; Daban et al., 2012). According to this study, WM exhibits
endophenotypic characteristics of bipolar disorder. A recent imaging
study also discovered that abnormalities in the body and splenium of the
corpus callosum may be an endophenotype for BD, and they link BD with
Aberrant white matter tracts associated with WM performance(Hu et al.,
2020) This study determined that the motion coordination in NSS was
consistent with endophenotype characteristics, and a longitudinal study
reached a similar conclusion, namely that dysfunctional manual motor
speed could be considered an endophenotype of BD(Correa-Ghisays P et
al., 2020).
When BP and HC samples are mixed, or FDR and HC samples are mixed,
motion coordination, IPS, VL, and WM are excellent predictors, and more
than 80% of the samples can be distinguished correctly. When
distinguishing between EBP and FDR, however, the accuracy decreases, and
only 62.3 % of individuals can be correctly identified. This may be
related to familial characteristics of endophenotypes, which enables
patients and their families more likely to display the endophenotype
than healthy individuals. In addition, the pathogenesis of the bipolar
disorder is complicated, involving multiple biological, psychological,
and environmental factors(Hu et al., 2022). When NSS and cognitive
deficit are used as predictors, it is therefore still difficult to
accurately distinguish patients from first-degree relatives. In future
research, it is hoped that biological and imaging markers will be
combined to create more complex and comprehensive potential phenotypes
and improve discrimination accuracy(Jiang et al., 2009; Segar et al.,
2021). However, this study found that motor coordination, IPS, VL, and
WM as predictors can accurately identify patients and first-degree
relatives from the healthy population. This result can be applied to
screening high-risk groups of bipolar disorder, so as to identify and
intervene early(Rabelo-da-Ponte et al., 2020), prevent disease
occurrence and improve disease prognosis(Correll et al., 2020).
Due to the cross-sectional design, we were unable to assess premorbid
cognitive functioning and NSS. Additionally, due to the complexity of
the medicine types utilized (including atypical antipsychotics and
emotional stabilizers), the effect of pharmaceuticals on NSS and
cognitive function evaluation findings has not been examined. However,
earlier research on bipolar disorder revealed no association between NSS
and neuropsychological evaluation findings and medications(Jiang et al.,
2022; Pitzianti et al., 2019).