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).