Major depressive disorder (MDD) is a worldwide widespread psychiatric disorder associated with premature death by suicide (Saraceno, 2002; Kalin, 2020). The lifetime risk of suicide in patients with MDD ranges from 5 to 11% (Angst et al., 2005; Isometsä, 2014). Approximately 40–70% of those who have attempted or committed suicide were diagnosed with major depressive disorder (Rihmer, 2007). Recent studies suggest that the lifetime prevalence of suicide attempts (SA) in MDD was as high as 31% worldwide (Dong et al., 2019). Although the social and personal costs of suicidal behavior are devastating, clinically, suicide risk in MDD patients is predicted based on a few limited scale tests. However, these tests are largely dependent on the subjective wishes of the patients. Also, patients may be inclined to avoid discussing SA with clinicians (Zalsman et al., 2016). Therefore, it is important to identify markers associated with SA, which may help to develop tests to assess the risk of suicide and also have the potential to create more targeted therapeutic strategies to reverse SA (Schmaal et al., 2020).

In an attempt to identify factors contributing to suicidal behavior, an increasing number of researchers have studied neurobiological markers pointing to functional and structural alterations in the limbic zone of MDD patients with suicidal behavior (Cao et al., 2016; Zhang et al., 2016). Meanwhile, previous studies also found that both psychotherapy (Chaïb et al., 2020) and psychoactive medication (Zalsman et al., 2016) could reduce the risk of suicide. However, there are no objective indicators to quantify this risk yet. Therefore, elucidating the neural basis of suicidal behavior in MDD may provide insights into early intervention and treatment. Resting state functional magnetic resonance imaging (rs-fMRI) studies have found that SA often occurs during mind rest phases, brain processes that occur when subjects are not engaged in any specific mental task (Rush and Beck, 1978). Previous studies showed that SA was associated with a pattern of low self-esteem (Cox et al., 2004; Bhar et al., 2008). Another study showed that two dimensions of rumination, brooding, and reflection, were predictors of suicidal ideation (Miranda and Nolen-Hoeksema, 2007). Moreover, rs-fMRI study explained the neural substrates of depressive rumination and explicit account of functional abnormalities in sgPFC in MDD (Hamilton et al., 2015). Therefore, rs-fMRI is particularly beneficial in finding SA in MDD related brain regions.

In magnetic resonance imaging (MRI), a powerful tool to explore alterations in neural circuits is regional homogeneity (ReHo), which reflects statistical similarity in spontaneous neural activity between spatially adjacent brain tissues (Zhu et al., 2005). ReHo is believed to reflect anatomical, morphological, and intrinsic geometric similarities and topological functional interactions of local brain structures. Abnormal ReHo reflects changes in the temporal aspects of regional neural activity (Jiang and Zuo, 2016). At present, the studies of brain function mainly focus on evaluating local functional changes, and ReHo is used as a measure of regional synchronization of the fMRI time course, and has been widely used in many studies on MDD. ReHo alterations in the prefrontal cortex, thalamus, right supplementary motor area, and primary visual, auditory, and motor cortices have been detected in MDD. A recent study found that lower ReHo in the postcentral gyrus was associated with depressive symptoms in MDD. In addition, a recent study (Xia et al., 2019) provided some evidence for differentiating subgroups of MDD. ReHo may be a transdiagnostic neurobiological basis for reproducible alterations in the assessment of underlying depressive symptoms.

Research has focused on investigating dynamic functional connectivity or networks, which can provide information about dynamic tissue changes in brain strength or space (Bassett and Sporns, 2017). Studies in depressed patients have linked SA to impulsive behavior and executive and emotional processing dysfunction (Myung et al., 2016; Johnston et al., 2017). Notably, executive functions and emotional processing involve brain regions such as the orbitofrontal cortex, anterior cingulate cortex, dorsolateral prefrontal cortex and temporal polar gyrus (Rogers et al., 2004; Olson et al., 2007). Frontal limbic (Du et al., 2017) and orbitofrontal thalamic functional connectivity (Kim et al., 2017) and frontal cortical white matter connectivity (Myung et al., 2016) were reduced in patients with SA compared to MDD patients without SA. Convergent findings suggest the presence of structural and fMRI abnormalities in MDD SA patients (Myung et al., 2016; Du et al., 2017; Kim et al., 2017). The reason for the inconsistency of these research results may be due to the limited research indicators or the different focus of the research objects, some teenagers (Ordaz et al., 2018) and women (Wei et al., 2018). However, there are a few promising studies (Cao et al., 2015; Chen et al., 2021) on suicide and ReHo indicators, which in turn encourages additional related research.

In an effort to characterize MDD patients with concomitant SA, we applied ReHo on resting state fMRI of MDD patients with and without SA. We sought to determine (1) whether MDD patients with SA show a different pattern of local consistency than MDD patients without SA and (2) whether the altered ReHo values could provide a neural marker to predict the severity of SA. By studying ReHo features in MDD patients with SA, we expect to delineate brain regions associated with SA that have the potential to be targeted for subsequent therapies. We also hope to shed further light on the biological details of the brains of MDD patients with SA.

We examined whether there were differences among the three groups in whole brain ReHo during a resting state. Subjects with SA showed a significant increase of in ReHo in the right Cingulum Post compared to those without SA. Subjects with SA showed a significant decrease of in ReHo in the right Cingulate Gyrus/Precuneus compared to HC. The mean ReHo from the significant brain region was associated with HAMD-SA scores (r = 0.349, P = 0.012) but was not associated with HAMD-24 scores.

At the initial assessment, because patients and clinicians may be relatively unaware of each other, suicide patients may deny SA during an interview. Some patients may deliberately obstruct interventions to prevent suicide (Brook et al., 2006). Identifying neurophysiologic markers is of great importance for objectively diagnosing SA in MDD patients. The results of our present study show that the SA group demonstrated increased local consistency of neural activity in the right cingulate relative to the NSA group; however, it demonstrated less local consistency in the right Cingulate/Precuneus relative to the HC group. In addition, the mean ReHo of right cingulate from the significant brain region correlated with the HAMD-SA score, but was not associated with HAMD-24 scores. Finding these ReHo-altered functional brain regions may shed light on the pathophysiological mechanism of suicide in MDD patients.

Cingulate has been the subject of intense research, with anterior cingulate cortex (ACC) volume loss being one of the most consistent findings (Arnone et al., 2012). ACC is involved in cognitive functioning and is executive functioning (Breukelaar et al., 2017), and impaired executive functioning may be a neuropsychological risk factor for suicidal behavior (Westheide et al., 2008). It has been reported that there was a volume decrease in the rostral anterior cingulate in patients with suicidal MDD compared to non-suicidal MDD patients (Wagner et al., 2011; Li et al., 2019). An autopsy study revealed that the number and length of dendritic branches in the anterior cingulate gyrus were significantly reduced in depressed suicide completers compared to controls (Hercher et al., 2010). A recent study reported decreased ACC activity in adolescents with a history of suicide attempts and depression compared to adolescents with a history of depression only (Pan et al., 2011). However, our study illustrates increasing right cingulate functioning in MDD patients with SA. Therefore, we speculate that the ReHo changes of ACC in depression and suicide should be similar, which may be related to the common pathophysiological mechanism of depression and suicide in this region.

Recent brain functional imaging studies have found that the precuneus is associated with many high levels cognitive functions, such as episodic memory, self-related information processing. Previous studies mostly focused on the local functional consistency of precuneus in depression, and little attention has been paid on suicide. Of the two suicide-related ReHo studies, one was that ReHo in the left precuneus was higher in the SA group than in the normal control group (Cao et al., 2015), the other study found lower ReHo of the right cuneus in the SA group compared with the NSA group (Chen et al., 2021). No such result was found in our study. However, there are many studies on ReHo indicators of depression. Liu et al. (2012) study found that compared to the healthy controls, MDD patients had significantly decreased ReHo in right precuneus. Moreover, other studies found that there were significant lower in ReHo in left anterior cingulate cortex and bilateral precuneus in MDD group compared with the control group (Lai, 2018). These are consistent with the results of our study. However, findings that are inconsistent with ours were reported, including those those in the study of Zhang et al. (2021) where it was shown that ReHo in the right precuneus lobe of patients with SA depression was significantly increased compared with healthy controls. Studies reported that relative to patients with LOD (later adult onset depression, age 30–44), patients with EOD (early adult onset depression, age 18–29) displayed significantly increased ReHo in the left precuneus (Chen et al., 2012; Shen et al., 2017). In our study, we did not have similar observations on the left precuneus, probably reflecting the idiosyncrasies of the different study subjects. The reason for the similarities and differences of these results may also be that precuneus is not necessarily a dysfunctional brain area caused by suicide, but may be a specific indicator of depression.

Regarding the correlation between ReHo and HAMD, a study found that the right cuneus of SI was positively correlated with HAM-D (Chen et al., 2021). Another study (Modinos et al., 2014) found that the volume of anterior cingulate gyrus negatively correlated with suicidal symptoms. The correlation analysis of another study (Zhang et al., 2021) showed that there was no significant correlation between the BDI-II score and the ReHo value of the precuneus in the SA group. Our study found that the mean ReHo in the right cingulate gyrus was correlated with HAMD-SA scores, but was not associated with HAMD-24 scores. It also indirectly illustrates that structural and functional abnormalities of the cingulate gyrus may be closely related to the symptoms of suicide.

Our study had some limitations: first, the sample size for MDD patients was relatively small. A larger sample size is needed to replicate the results we presented here. Second, our study was a cross-sectional design, and the data were insufficient to establish a causal relationship between depressive symptoms and suicidal behavior. Future studies using longitudinal designs will be useful for examining the causal relationship between depression and SA. Third, we only studied suicidal ideation in MDD patients. Future studies are needed to examine the role of the right cingulate gyrus in suicidal behavior in patients with other mental disorders, such as schizophrenia. Last but not least, it has been demonstrated that periods of untreated depression are associated with greater volume loss in some brain regions. We will certainly pay attention to this point in future studies. Therefore, our findings should be considered preliminary and should be confirmed before firm conclusions can be drawn.

Our study showed that SA in depressed patients was associated with alterations in resting state brain activity. Our results suggest that the neural basis of psychopathology in depressed patients with suicidal ideation may involve functional abnormalities in multiple brain regions. The pattern of increased local functional activity in the right cingulate may be related to SA. Identifying cingulate activity may help elucidate the etiology and pathogenesis associated with SA.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Medical Research Ethics Committee of Shanxi Medical University. The patients/participants provided their written informed consent to participate in this study.

KZ and ZL designed and supervised this study. NS, YW, GL, and CY were responsible for data analysis and manuscript drafting. PL and LL revised the manuscript. YD and AZ participated in sample collection and carried out the experimental procedures. All authors reviewed and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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