Structural alterations associated with suicide attempts in major depressive disorder and bipolar disorder: A diffusion tensor imaging study

Progress in Neuropsychopharmacology & Biological Psychiatry 98 (2020) 109827

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Structural alterations associated with suicide attempts in major depressive disorder and bipolar disorder: A diffusion tensor imaging study

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Shengnan Weia,b, Fay Y. Womerc, Elliot K. Edmistond, Ran Zhange, Xiaowei Jianga,b, Feng Wue, ⁎ ⁎ Lingtao Konge, Yifang Zhoue,f, Yanqing Tange,f, , Fei Wanga,b,e, a

Brain Function Research Section, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China Department of Radiology, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA d Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA e Department of Psychiatry, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China f Department of Geriatric Medicine, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China b

A R T I C LE I N FO

A B S T R A C T

Keywords: Suicide attempts Major depressive disorder Bipolar disorder Diffusion tensor imaging

Background: Major depressive disorder (MDD) and bipolar disorder (BD) are major affective disorders associated with high risk for suicide. Neural mechanisms underlying suicide attempts are poorly understood in MDD and BD but likely relate to the structural abnormalities in brain regions. In this study, we explored structural alterations in MDD and BD with prior suicide attempts (SA) using diffusion tensor imaging (DTI). Methods: Participants consisted of 27 MDD patients with prior SA (men: 9; age means ± sd: 28.04 ± 11.06 years), 49 MDD patients without prior SA (men: 11; age means ± sd: 30.03 ± 0.91 years), 25 BD patients with prior SA (men: 7, age means ± sd: 27.08 ± 8.40 years), 49 BD patients without prior SA (men: 26, means ± sd: 27.69 ± 9.97 years)，and 49 healthy controls (HC) (men: 18, means ± sd: 31.12 ± 9.95 years). All participants underwent DTI to examine fractional anisotropy (FA) in brain regions. Results: FA in several major white matter (WM) bundles including bilateral inferior fronto-occipital fasciculus (IFOF), bilateral uncinate fasciculus (UF), and the corpus callosum (CC) was shown in MDD with prior SA, compared to MDD without prior SA and HC. Decreased FA was also found in bilateral IFOF, bilateral UF, and CC, as well as other WM bundles, in BD with prior SA, compared to BD without prior SA and HC. Significant diagnostic group by SA effects were shown in bilateral thalami with lowest mean FA values in MDD with prior SA. Conclusions: Our findings support the involvement of structural alterations in suicide attempts in major affective disorders. Shared and distinct structural alterations were shown in MDD and BD with prior SA, suggesting common and differential neural pathways for suicide among major affective disorder.

1. Introduction Suicide represents a major public health crisis worldwide. More than 800,000 people die by suicide around the world every year, and about 20 times more suicide attempts (SA) (Hegerl, 2016). In China, suicide is the fifth most common cause of death, accounting for approximately 287,000 deaths per year (Phillips et al., 2002). SA is a strongly risk factor for suicide death (Brown et al., 2000). Major depressive disorder (MDD) and bipolar disorder (BD) as the two most common affective disorders are closely associated with high risk for suicidality suicidality (including suicide death, suicide attempts, suicidal ideation). Epidemiological studies show that 29% of individuals

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with a diagnosis of BD and 15% of those with MDD attempt suicide at least once in their lifetime (Chen and Dilsaver, 1996), and approximately 10–15% of patients with BD and 2–12% of patients with MDD have lifetime risk of dying by suicide (Bostwick and Pankratz, 2000; Sinclair et al., 2005). Unfortunately, current strategies to accurately predict suicide are lacking. At present, there is heavy reliance on patient self-report, observation of patient behavior, and clinician judgment. Key features of suicide have been identified through epidemiology. For example, SA in MDD is strongly related with major depressive episodes (Holma et al., 2010; Riihimaki et al., 2014), while BD patients with prior SA exhibit high impulsivity and aggression (Swann et al., 2005; Swann et al.,

Corresponding authors at: Department of Psychiatry, First Affiliated Hospital, China Medical University, Shenyang, Liaoning, PR China. E-mail addresses: [email protected] (Y. Tang), [email protected] (F. Wang).

https://doi.org/10.1016/j.pnpbp.2019.109827 Received 17 July 2019; Received in revised form 15 November 2019; Accepted 23 November 2019 Available online 25 November 2019 0278-5846/ © 2019 Published by Elsevier Inc.

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respectively, and did not meet criteria for any other Axis I disorder. HC participants did not have current or lifetime Axis I disorder or a history of psychotic, mood, other Axis I disorders, or a history of SA in firstdegree relatives as determined by a detailed family history. All subjects were evaluated using the Hamilton Depression Rating Scale (HAM-D) and Young Mania Rating Scale (YMRS). Participants were excluded if they had substance/alcohol abuse/dependence or a concomitant major medical disorder, any MRI contraindications, history of head trauma with loss of consciousness for ≥5 min, or any neurological disorder. Then, MDD/BD patients were divided into with and without prior SA group. Prior SA was defined as history of at least one attempt defined as a self-destructive act with some degree of intent to die (Oquendo et al., 2004) and patients without prior SA (i.e., non-attempters; no such history). Subjects were not considered suicide attempters if their selfinjurious behavior was determined to have no suicidal intent. Finally, the study included 199 subjects aged 15–49 years divided into five groups: 27 MDD patients with prior SA (mean age: 28.04 ± 11.06 years; 18 females), 49 MDD patients without prior SA (mean age: 30.03 ± 0.91 years; 38 females), 25 BD patients with prior SA (mean age: 27.08 ± 0.40 years; 18 females), 49 BD patients without prior SA (mean age: 27.69 ± 9.97 years; 23 females), and 49 HC individuals (mean age: 31.12 ± 9.95 years; 31 females). All participants provided written informed consent after detailed description of the study. If participants were younger than 18 years old, participants gave written informed assent, and their parent/legal guardian provided written informed consent after receiving a detailed description of the study. This study was approved by the Institutional Review Board of China Medical University.

2009). However, further understanding of these features from neural perspective is limited but needed to improve suicide risk screening and risk assessment. Recent review or meta-analysis of the literature demonstrated the structural and functional brain abnormalities in suicide attempters with MDD and BD (Bani-Fatemi et al., 2018; Dong et al., 2019). In specifically, structural brain studies have indicated that MDD patients with a history of SA (in contrast to those without a history of SA and healthy controls [HC]) may have reduced hippocampal volume (Colle et al., 2015), abnormalities in the parietal cortex (Chen et al., 2015), frontocingulo-striatal network (Wagner et al., 2012), the caudate, rostral anterior cingulate cortex (Wagner et al., 2011), temporal–parietal–limbic networks (Hwang et al., 2010), left angular gyrus (Lee et al., 2016), and right superior temporal gyrus (McLellan et al., 2018; Pan et al., 2015). Then, initial studies of suicidal behavior in BD focusing on the association between SA and impulsivity indicated that the corpus callosum may be involved in the pathophysiology of impulsive and suicidal behaviors (Matsuo et al., 2010; Nery-Fernandes et al., 2012). Other structural brain studies have shown that BD with a history of SA is related to abnormalities of gray matter volume in the right rostral anterior cingulate cortex (Duarte et al., 2017), and the ventral frontolimbic system implicated in emotion regulation (Johnston et al., 2017). Especially, neuroimaging evidence also supports that abnormalities of white matter (WM) may be closely related to patients in MDD and BD with suicide attempts. For example, white matter hyperintensities (WMH) showed that their prevalence was significantly higher in depressed patients with past SA compared to subjects without SA (Ehrlich et al., 2005). Diffusion tensor imaging (DTI) studies have suggested that MDD patients with a history of SA display greater abnormalities in the left orbitofrontal cortex, thalamus (Jia et al., 2014), and left anterior limb of the internal capsule (ALIC) (Jia et al., 2010) than those without. Recent neuroimaging of frontolimbic structure and function in BD patients with SA demonstrated significant reductions in WM integrity in the uncinate fasciculus, ventral frontal, and right cerebellum regions, and its sample only involved adolescent and young adults, which revealed importance in terms of WM development related to SA (Johnston et al., 2017). In this study, we examined structural alterations as reflected by fractional anisotropy (FA) in MDD and BD patients with and without prior SA using DTI, which measures diffusion characteristics of water molecules in vivo to assess WM integrity (Taylor et al., 2004). FA, the most widely employed DTI index, estimates the directionality and continuity of the white matter tracts. We hypothesized that there would be common alterations in FA values between MDD and BD patients with a history of SA, because (1) suicide may exist which is independent of the disorder itself, and (2) MDD and BD may have similar pathological mechanisms as two affective disorders. However, we also hypothesized that there may be differences in FA values between these patients, because they are two diseases with different symptoms, although they shared the suicidal behavior.

2.2. MRI acquisition MRI data were obtained with the GE Signa HDx 3.0T scanner at the Department of Radiology, First Affiliated Hospital of China Medical University, Shenyang, China. All participants underwent DTI with following parameters: repetition time = 17,000/85.4 ms, image matrix = 120 × 120, field of view = 240 × 240 mm2, 65 contiguous slices of 2 mm without gap, 25 noncollinear directions (b = 1000 s/ mm2), together with an axial acquisition without diffusion weighting (b = 0), and voxel size = 2.0 mm3. 2.3. Data processing DTI data were processed using Pipeline for Analyzing braiN Diffusion imAges software (http://www.nitrc.org/projects/panda). We applied standard procedures suggested by Ashburner (Ashburner and Friston, 2000) and Cui (Cui et al., 2013). First, the voxel-wise diffusion tensor matrix was calculated for each subject in the native space. Next, diagonalization was performed to yield three pairs of eigenvalues and eigenvectors. Based on the three eigenvalues, FA was computed on a voxel-by-voxel basis. Specifically, the FA image of each subject was nonlinearly registered to the FMRIB58_FA template in the Montreal Neurological Institute (MNI) space with 2 mm3 voxels. The mean of all aligned FA images was then calculated. FA images were then smoothed with a 6 mm full width at half maximum Gaussian filter.

2. Materials and methods 2.1. Subjects At first, all patients were from Shenyang Mental Health Center and the Department of Psychiatry, First Affiliated Hospital of China Medical University, Shenyang, China. HC were recruited from advertising within the community. All participants were evaluated by two trained psychiatrists to determine the presence or absence of Axis I psychiatric diagnoses using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Axis I Disorders (SCID) in those 18 years old and older and the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL) in those younger than 18 years. MDD and BD participants met DSM-IV diagnostic criteria for MDD and BD,

2.4. Statistical analyses DTI data were analyzed using SPM8 (www.fil.ion.ucl.ac.uk/spm/ software/spm8). To determine if the differences in WM tracts between groups were statistically significant, we used a one-way ANOVA with age and sex as covariates between the MDD patients with a history of SA, MDD patients without a history of SA, and HC groups. Statistical significance was determined by P < .001 (corrected, Gaussian random field [GRF] correction), and an extent threshold of 51 voxels was considered significant among the MDD with and without a history of SA and HC groups. Using the same method as above, an extent threshold of 2

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Table 1 Demographics and clinical characteristics of all participants. Variables

MDD with prior SA (n = 27)

MDD without prior SA (n = 49)

BD with prior SA (n = 25)

BD without prior SA (n = 49)

HC (n = 49)

F/χ2

P

Age (Mean ± SD) Age range (n, %) 15–24 25–40 41–49 Gender, male (n, %) Education (Mean ± SD) Duration (months; Mean ± SD) Medication, yes (n, %) Antidepressants Antipsychotics Mood stabilizer State Depressed Manic Remitted/stable HAM-D (Mean ± SD) YMRS (Mean ± SD)

28.04 ± 11.06

30.03 ± 0.91

27.08 ± 8.40

27.69 ± 9.97

31.12 ± 9.95

14 (51.90%) 8 (29.60%) 5 (18.50%) 9 (33.33%) 12.85 ± 3.07 18.48 ± 22.84

10 (20.40%) 34 (69.40%) 5 (10.20%) 11 (22.45%) 13.48 ± 2.95 27.07 ± 49.53

9 (36.00%) 14 (56.00%) 2 (8.00%) 7 (28.00%) 13.56 ± 2.66 26.52 ± 29.66

21 (42.90%) 24 (49.00%) 4 (8.20%) 26 (53.10%) 12.61 ± 2.66 32.74 ± 43.13

18 (36.70%) 26 (53.10%) 5 (10.20%) 18 (36.73%) 13.55 ± 2.94 –

1.36 13.75 – – – 10.92 1.02 0.55

0.25 0.09 – – – 0.03 0.40 0.65

19 (70.40%) 18 (66.67%) 2 (7.41%) 0

28 (57.10%) 25 (51.02%) 2 (4.08%) 1 (2.04%)

20 11 12 11

36 25 16 20

19 (70.40%) 0 8 (29.60%) 18.67 ± 9.86 1.88 ± 4.49

37 (75.50%) 0 12 (24.50%) 20.41 ± 9.08 1.18 ± 2.55

11 (44.00%) 8 (32.00%) 6 (24.00%) 13.30 ± 11.34 7.00 ± 9.45

– – – – – – – – 1.33 ± 1.71 0.29 ± 0.78

5.08 – – – – – –

0.17 – – – – – –

– –

– –

(80.00%) (44.00%) (48.00%) (44.00%)

(73.50%) (51.02%) (32.65%) (40.81%)

27 (55.10%) 12 (24.50%) 10 (20.40%) 11.39 ± 8.36 6.46 ± 9.19

Note: MDD: major depressive disorder; SA: suicide attempts; BD: bipolar disorder; HC: healthy controls; SD: standard deviation; HAM-D: Hamilton Depression Rating Scale; YMRS: Young Manic Rating Scale.

without prior SA) vs. HC group to clarify the transnosographic potential of this study (see Supplemental File).

46 voxels was considered significant among the BD with and without a history of SA and HC groups. We then extracted FA values for each cluster with significant differences for the three group comparison and conducted pairwise two sample t-tests, corrected for multiple comparisons (P < .05, Least Significant Difference [LSD] test). In addition, the data were also analyzed by two-way ANOVA with diagnosis (MDD/BD) and SA (with/without) as component variables to examine their effects on changes of WM tracts using SPM8 and DPABI software, with age and sex as covariates. Significant diagnostic group by SA interactions were determined by P < .001 (corrected, GRF correction). We then extracted FA values for each cluster with significant differences for five groups (including HC group), and further observed the variation in FA values by post hoc multiple comparisons (P < .05, LSD test).

3.2. WM integrity in MDD and BD with prior SA Significant FA differences were shown in six clusters among MDD and HC groups (Table 2, Fig. 1A). Post hoc comparisons found significantly decreased FA in bilateral inferior fronto-occipital fasciculus (IFOF), bilateral uncinate fasciculus (UF), the body of the corpus callosum (CC), right anterior limb of internal capsule (ALIC), right external capsule, left posterior thalamic radiation, and bilateral posterior corona radiate in MDD with prior SA, compared to MDD without prior SA and HC (Fig. 2A). Among BD and HC groups, significant FA differences were found in eight clusters (Table 3, Fig. 1B). Post hoc analyses showed significantly decreased FA in bilateral IFOF, bilateral UF, the body of CC, right ALIC, right external capsule, left posterior corona radiate, and left posterior thalamic radiation in BD with prior SA, compared to BD without prior SA and HC (Fig. 2B).

3. Results 3.1. Demographics and clinical characteristics Table 1 shows detailed participant demographic and clinical data. There were no significant differences in age (F = 1.36, P = .25) and education (F = 1.02, P = .40) among MDD/BD with and without prior SA and HC groups. There was a significant difference in sex in BD without prior SA group than in BD with and MDD with/without prior SA and HC groups (χ2 = 5.08, P = .03), however, MDD/BD with and without prior SA and HC groups were not significantly different in terms of sex (MDD with and without prior SA and HC groups: χ2 = 2.50, P = .29; BD with and without prior SA and HC groups: χ2 = 5.03, P = .08). Duration of illness (F = 0.55, P = .65) and medication status (χ2 = 5.08, P = .17) were not significantly different among MDD/BD with and without prior SA groups. MDD with and without prior SA and HC groups showed significantly difference in HAM-D scores (F = 82.18, P = .000), and no difference in YMRS scores (F = 2.79, P = .07). But post hoc analyses found the MDD with and without prior SA groups showed no significantly difference in HAM-D scores. BD with and without prior SA and HC groups showed significantly difference in HAM-D scores (F = 27.61, P = .000), and YMRS scores (F = 9.63, P = .000). However, post hoc analyses found the BD with and without prior SA groups showed no significantly difference in HAM-D scores and YMRS scores. We also compared (MDD with prior SA + BD with prior SA) vs. (MDD without prior SA + BD

Table 2 Brain regions showing significant changes in WM between MDD with and without prior SA and HC groups. Index

CL1A

CL2A

CL3A

CL4A

CL5A CL6A

Region

Left inferior fronto-occipital fasciculus Left uncinate fasciculus Right inferior fronto-occipital fasciculus Right uncinate fasciculus Right anterior limb of internal capsule Right external capsule Left posterior thalamic radiation Left posterior corona radiata Body of corpus callosum Right posterior corona radiata

Voxel

F values⁎

MNI coordinates X

Y

Z

325

−34

0

−16

46.51

250

34

2

−16

36.85

222

20

12

16

12.46

113

−34

−60

20

13.44

66 58

−2 32

6 −60

20 26

13.89 12.50

Note: MNI: Montreal Neurological Institute. ⁎ Significant at P < .001 corrected by Gaussian random field correction. 3

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Fig. 1. (A) Significant differences in fractional anisotropy (FA) values among the major depressive disorder (MDD) with prior suicide attempts (SA), MDD without prior SA, and healthy controls (HC) groups. Significant at P < .001, corrected by Gaussian random field (GRF) correction. (B) Significant differences in FA values among the bipolar disorder (BD) with prior SA, BD without prior SA, and HC groups. Significant at P < .001, corrected by GRF correction.

Fig. 2. (A) Post hoc analysis of fractional anisotropy (FA) values among the major depressive disorder (MDD) with prior suicide attempts (SA), MDD without prior SA, and healthy controls (HC) groups. (***P < .001; **P < .01; *P < .05). (B) Post hoc analysis of FA values among the bipolar disorder (BD) with prior SA, BD without prior SA, and HC groups. (***P < .001; **P < .01; *P < .05). CL1A/CL1B: Left inferior fronto-occipital fasciculus and uncinate fasciculus; CL2A/CL2B: Right inferior fronto-occipital fasciculus and uncinate fasciculus; CL3A/CL3B: Right anterior limb of internal capsule and external capsule; CL4A: Left posterior thalamic radiation and posterior corona radiate; CL5A: Body of corpus callosum; CL6A: Right posterior corona radiate; CL4B: Left posterior thalamic radiation; CL5B/CL6B/CL7B: Body of corpus callosum; CL8B: Left posterior corona radiate.

4

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Table 3 Brain regions showing significant changes in WM between BD with and without prior SA and HC groups. Index

CL1B

CL2B

CL3B

CL4B CL5B CL6B CL7B CL8B

Region

Left inferior fronto-occipital fasciculus Left uncinate fasciculus Right inferior fronto-occipital fasciculus Right uncinate fasciculus Right anterior limb of internal capsule Right external capsule Left posterior thalamic radiation Body of corpus callosum Body of corpus callosum Body of corpus callosum Left posterior corona radiata

Voxel

F values⁎

MNI coordinates X

Y

Z

315

−34

2

−16

11.09

152

34

2

−16

32.86

220

28

16

−6

13.33

52

−22

−70

12

17.80

76 89 99 51

8 −6 4 −18

18 −14 −4 −36

18 28 30 36

9.83 12.95 10.87 12.02

Note: MNI: Montreal Neurological Institute. ⁎Significant at P < .001 corrected by Gaussian random field correction.

3.3. Diagnostic group by attempts effect on FA Significant diagnostic group by SA effects were found on FA in bilateral thalami (left thalamus: cluster size = 51 voxels, maximal point MNI coordinate: x = −10 mm, y = −12 mm, z = 10 mm, F = 19.02; right thalamus: cluster size = 18 voxels, maximal point MNI coordinate: x = 12 mm, y = −10 mm, z = 10 mm, F = 17.53, P < .001, corrected by GRF correction; Fig. 3). Post hoc two-sample ttests indicated MDD with prior SA had significantly decreased FA in bilateral thalami, compared to HC group. FA values in bilateral thalami in the BD with prior SA was not statistically significant than those in the HC group. However, the average value of the FA values in BD with prior SA group was higher in bilateral thalami compared to HC group. 4. Discussion Fig. 3. (A) Brain regions of diagnosis by suicide attempts (SA; with/without) in major depressive disorder (MDD) compared to bipolar disorder (BD). Significant at P < .001 corrected by GRF correction. (B) Fractional anisotropy (FA) values in the regions showing significant interaction of diagnosis by SA (with/without) from two-way analysis of variance among five groups (MDD/BD with prior SA, MDD/BD without prior SA, and healthy controls (HC)) (*P < .05).

To our knowledge, this is a rare study to compare WM integrity differences associated with SA in MDD and BD at present. We found substantial commonalities in WM alterations between MDD and BD with prior SA relative to HC, although differences were observed in the thalamus between MDD and BD groups with prior SA. This discovery proves that suicide may have its own mechanism of independent of the disorder which need future study to explore. These findings also suggest shared pathways for suicidality in MDD and BD. MDD and BD are affective disorders that maybe share pathophysiological mechanism. They share clinical features such as depression, anxious, irritability (Benazzi, 2006; Schaffer et al., 2010), and cognitive dysfunction (Cotrena et al., 2017). Recent studies of a genetic database and a metaanalysis of MDD and BD indicated that they had largely overlapping genetic influences (Chang et al., 2013; Gatt et al., 2015). Furthermore, structural neuroimaging meta-analytical studies also show that they share common changes in some brain regions (Kempton et al., 2011; Wise et al., 2016). Our previous structural magnetic resonance imaging (MRI) study among three major psychiatric diagnostic categories also indicated common alterations in MDD and BD (Chang et al., 2018). Genetic and neuroimaging studies on the pathogenesis of BD and MDD are ambiguous and further research is needed. However, MDD and BD are clinically distinct psychiatric illnesses so that they may also have different pathological mechanism for suicidality. For their shared WM alterations, especially, the following brain regions are important and worth discussing. On one hand, the abnormalities in the bilateral IFOF, bilateral UF, right ALIC may be associated with SA in MDD and BD, would serve as biomarkers of SA in

MDD and BD. On the other hand, the alterations in the body of corpus callosum may be related to the pathogenesis of suicide itself. These specific features may indicate important imaging biomarkers of suicidal behavior in mood disorders. This further illustrates that the alterations in the body of corpus callosum may be a biological marker unique to suicide itself. Firstly, the IFOF is involved in emotional visual function and considered to play key roles in the frontal-subcortical circuits. Previous studies in MDD and BD patients indicated that the FA values in the bilateral IFOF were significantly decreased compared to those in the HC group (Ota et al., 2015; Saricicek et al., 2016; Sugimoto et al., 2018), which is consistent with our results. However, the most important is that the alterations in the IFOF may be related to suicidal behavior in MDD and BD from our results and other studies have not been reported this finding. So how the IFOF works in the pathophysiology of suicidal behavior in MDD and BD is still unclear and needs the next study to verify and explain. Secondly, the UF is an anterior WM structure and has been implicated in emotional and cognitive processing (Papagno et al., 2011; 5

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shown that suicidal behavior is closed related to impulsivity in BD patients, indicating that those with suicidal behavior also exhibit high impulsivity (Swann et al., 2005; Swann et al., 2009). So we considered that suicidal behavior in BD patients may be related to impulsive behaviors. Together with the understanding that increased thalamic activity is closely associated with motor impulsivity, we can explain that the increased thalamic activity in BD patients may cause impulsive behavior, which may further result in suicidal behavior. This evidence indicates that the thalamus may be a biological trait marker for suicidal behavior in BD. There are several limitations to this study. Firstly, it seems the sample size was sufficient to detect several abnormalities. However, we hope to prove these results with a larger sample for future research in future study. Secondly, psychotropic medications and duration of illness may affect the results to a greater or lesser extent, and there is no statistical difference in medications and duration of illness between MDD with prior SA and without SA, BD with prior SA and without SA, which minimize the impact of medications and duration of illness. Additionally, the age range was from 15 to 49 years, and we used age as a covariate and described the specific distribution of age to reduce the age affection to our results. Finally, the interaction findings that showed minor different abnormalities between MDD and BD patients with a history of SA may not be accurate because of the limitations of methodology itself. Thus, longitudinal and specific research is required to better understand the complex relationship between neuroanatomy, suicidal behavior, and mood disorders.

Von Der Heide et al., 2013). Increasing evidence implicates abnormalities in UF in MDD and BD(Lin et al., 2011; Liu et al., 2016; Saricicek et al., 2016; Won et al., 2017). Szebeni reported that relative telomere length was significantly lower in oligodendrocytes obtained from the UF of MDD donors who primarily died by suicide than in healthy, agematched, control donors (Szebeni et al., 2014), which indicates that lesions in UF WM may be related to MDD with suicidal behavior. A previous DTI study in BD with SA also showed that the SA group showed significant reductions in WM integrity in the UF compared with the non-attempter group (Johnston et al., 2017). These results correspond with our findings that abnormalities in the UF are important in the neurobiological mechanism of suicidality in MDD and BD. Thirdly, DTI studies indicate that patients show reduced FA in the ALIC in MDD and BD (Dillon et al., 2018; Lu et al., 2012), and patients with MDD who have a history of SA also showed decreased FA in the ALIC (Jia et al., 2010). The ALIC is thought to be involved with the processing of emotional information by the limbic system and mood regulation (Lu et al., 2012; Malone Jr. et al., 2009); thus, we speculate that the ALIC may be closely related to suicidality in BD because MDD and BD shared etiology and pathogenesis. Fourthly, our findings suggest that alterations in the body of corpus callosum are related to the suicidal behavior in these two disorders. A recent DTI study showed that corpus callosum integrity is specifically altered in suicide attempters in mood disorders, independently from their psychiatric status, and the mean FA values in the corpus callosum regions (including the body of the corpus callosum) in MDD or BD patients with a history of SA was lower than in HC (Cyprien et al., 2016). Although their sample was all women, their results are consistent with our findings. With regard to their distinct abnormalities in FA values, the MDD with prior SA group had lower FA values in WM integrity in the left and right thalamus than in HC, and the average FA values in the left and right thalamus in the BD with prior SA group was higher than in HC, so these different alterations in thalamus may be associated with SA features specific to MDD and BD. The cause of this result may be closely related to the function of the thalamus itself. At first, The thalamus is involved in emotion regulation and has been found to exhibit a decrease in duration of activation (De Raedt et al., 1997; Waugh et al., 2016). The thalamus provides a relay through which sensory and other types of information can reach core emotion and emotion regulation areas. This suggests that decreasing the duration of activation in the thalamus during reappraisal might be an effective way of limiting emotion-related information from reaching core emotional regions (Waugh et al., 2016). Two recent meta-analyses also demonstrated that the thalamus is important in emotion regulation in MDD patients (Arnone et al., 2016; Miller et al., 2015). Several additional studies have demonstrated that suicidal behavior in MDD patients may be deeply related to some symptoms, such as depression and feelings of worthlessness (Sokero et al., 2005; Wakefield and Schmitz, 2016). Decreased activity of the thalamus may lead to abnormal emotion regulation in MDD patients, especially in the regulation of negative emotions, which may further result in suicidal behavior. A recent study also found that thalamic activity and suicidal behavior in MDD patients were correlated (Jia et al., 2014). These results suggest the thalamus may be a powerful neuropathological basis of suicidal behavior in MDD. Meanwhile, the average value of the FA values in BD with prior SA group was higher in bilateral thalami compared to HC group. To some extent, we may speculate that the thalamus may be associated with SA in patients with BD. Thalamus is also closely associated with motor impulsivity. For example, recent studies from rat models have shown that lesions of the thalamic reuniens caused impulsivity (Amlung et al., 2014), and provided new insights into dopamine signaling in the lateral thalamus in decisional impulsivity (Wang et al., 2017). In human subjects, several studies have also demonstrated that human impulsive behavior was deeply related to more activity in the thalamus (Amlung et al., 2014; Miedl et al., 2015; Panwar et al., 2014). Previous studies also have

5. Conclusions Suicide appears to have both shared and distinct structural alterations in MDD and BD, suggesting common and differential pathways for suicide in mood disorders. Further investigations are warranted to determine how the commonalities and distinctions could serve as biomarkers of suicidality in MDD and BD. Such biomarkers are critical for effective suicide risk screening and prevention. Ethical statement The study was performed in accordance with the latest version of the Declaration of Helsinki and approved by the ethics committee of the Institutional Review Board of China Medical University. All participants provided written informed consent before taking part in this study. Authors' contribution SNW and FW designed the experiment. RZ, PSW, XWJ, ZYY and FW carried it out. YFZ and LTK analyzed the data. YQT and SNW wrote the manuscript. EKE and WYF edited the manuscript. All the authors discussed the results and reviewed the manuscript. Declaration of competing interest The authors declare no conflict of interest. Acknowledgments This work was supported by grants from the National Natural Science Foundation of China (81701336 to Shengnan Wei, 81271499 and 81571311 to Yanqing Tang, 81725005 and 81571331 to Fei Wang), the Liaoning Education Foundation (L2015591 to Shengnan Wei), Liaoning Pandeng Scholar (to Fei Wang), National Keyresearch and Development Program (2016YFC0904300 to Fei Wang), National High Tech Development Plan (863) (2015AA020513 to Fei Wang) and National Keyresearch and Development Program (2016YFC1306900 to Yanqing Tang). We would like to thank the patients and family members who contributed so much to this study and the First Affiliated 6

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Hospital of China Medical University for its active support of the project.

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