Journal of Affective Disorders 165 (2014) 69–73
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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Increased suicide attempts in young depressed patients with abnormal temporal–parietal–limbic gray matter volume Hongjun Peng a,n,1, Kai Wu b,nn, Jie Li a, Haochen Qi b, Shengwen Guo b, Minyue Chi b, Xiaoming Wu b, Yangbo Guo a, Yuling Yang a, Yuping Ning a,1 a b
Guangzhou Psychiatric Hospital, Affiliated Hospital of Guangzhou Medical University, Guangzhou, China Department of Biomedical Engineering, School of Materials Science and Engineering, South China University of Technology, Guangzhou, China
art ic l e i nf o
a b s t r a c t
Article history: Received 30 November 2013 Received in revised form 18 March 2014 Accepted 17 April 2014 Available online 24 April 2014
Background: Suicide is a major cause of death throughout the world. Approximately 60% of all suicides have a history of depression. Previous studies of structural brain imaging have shown that suicide is often associated with abnormal fronto-limbic networks. However, the mechanism underlying suicide in depression remains poorly understood. Method: Twenty sex- and age-matched suicidal unipolar patients were compared with 18 non-suicidal unipolar patients and 28 healthy controls. High-resolution T1-weighted 3 T magnetic resonance imaging (MRI) scans were acquired. Hamilton Depressive Rating Scale (HAMD) and Self-Rating Depression scale (SDS) were evaluated. The criterion for suicidality was one or more documented lifetime suicide attempts. A whole-brain optimized voxel-based morphometry (VBM) approach was applied. The Dysfunctional Attitude Scale (DAS) was used to measure cognitive scheme in depressive patients. Results: Compared with controls, patients without suicide history showed significant decreased gray matter volume in the left insula lobe [ 35 18 9], whereas patients with suicide history showed significantly decreased gray matter volume in the right middle temporal gyrus [60 53 8] and increased gray matter volume in the right parietal lobe [39 39 60]. Compared with the non-suicidal depressed patient group, the suicidal group showed significant decreased gray matter volume in left limbic cingulated gyrus [ 2 21 28]. Moreover, the gray matter volume values in this significantly different brain region were negatively correlated with dysfunctional attitude scores in suicidal depressed patients. Limitations: This study needs replication and further clarification in a larger patient population. Conclusions: Suicide attempts in young depressed patients may be related to abnormal gray matter volumes in temporal–parietal–limbic networks. Specifically, small left limbic cingulate gyrus volumes may be a candidate for the prediction of suicide in young depressed patients. & 2014 Elsevier B.V. All rights reserved.
Keywords: Depression Voxel based morphometry (VBM) Gray matter volume Suicide attempt
1. Introduction Suicide is a major cause of death throughout the world and is becoming a significant public health issue. Approximately 15 per
Abbreviations: ACC, Anterior cingulate cortex; ANOVA, Analysis of variance; CSF, Cerebrospinal fluid; DAS, Dysfunctional Attitudes Scale; FDR, False discovery rate; GLM, General Linear Model; GM, Gray matter; HAMD, Hamilton Depressive Rating Scale; LOD, Late onset depression; MDD, Major depression disorder; MRI, Magnetic resonance imaging; PFC, Prefrontal cortex; RGMV, Analysis of regional gray matter volume; ROI, Region-of-interest; SCID, Structured clinical interview; SDS, SelfRating Depression scale; SSRIs, Selective serotonin reuptake inhibitors; VBM, Voxel based morphometry. n Corresponding author. Tel.: þ 86 20 81268184; fax: þ 86 20 81891391. nn Corresponding author. Tel.: þ 86 20 3938 0660. E-mail addresses: [email protected] (H. Peng), [email protected] (K. Wu). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.jad.2014.04.046 0165-0327/& 2014 Elsevier B.V. All rights reserved.
100,000 individuals commit suicide each year, and 10–20 times more engage in non-fatal suicidal behavior (Kerkhof, 2000; Krug et al., 2002; van Heeringen et al., 2010). Sixty per cent of people who commit suicide have a history of depressive disorder (Carlson et al., 1991; Lee and Kim, 2011). The mechanism underlying suicide in depression remains unclear. Preclinical studies using animal models, and neuroendocrine and neurobiological studies of suicide cases, have mainly focused on the serotonin system (Mann et al., 2000; Owen et al., 1986; Stoff and Mann, 1997). Recent advances in magnetic resonance imaging (MRI) techniques have provided a noninvasive method by which to explore the cause of suicide in vivo. Structural brain imaging studies in suicidal patients with major depressive disorder (MDD) have found abnormal gray matter volumes or densities in suicide attempters; in particular, smaller volumes of the hippocampus, dorsolateral prefrontal cortex,
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orbitofrontal cortex, anterior cingulate, superior temporal cortex, parieto-occipital cortex, and basal ganglia (Ahearn et al., 2001; Desmyter et al., 2010; Hwang et al., 2010; Mann, 2005; Marchand et al., 2012; Monkul et al., 2007; Wagner et al., 2011). A previous study showed that long-term lithium treatment could improve gray matter volume deficit in suicidal patients (Benedetti et al., 2011). Previous studies have mainly focused on late onset depression (LOD; defined as onset over age 50) or elderly patients with MDD, and suggested that the total volume of frontal lobe in patients may be smaller than that in healthy controls (Figiel et al., 1991; Howard et al., 1993; Pompili et al., 2010). Subcortical gray matter hyperintensities have also been noted in the basal ganglia of LOD patients (Iidaka et al., 1996; Steffens et al., 1999). In addition, atrophy often occurs in the basal nuclei, cerebellum, and brainstem in elderly patients with depression. To our knowledge, very few studies have explored the changes in gray matter in young suicidal depressed patients, and few previous studies have found abnormal gray matter volumes in the temporal or parietal lobes in suicidal psychiatric patients (Aguilar et al., 2008; van Heeringen et al., 2010). Therefore, the purpose of the present study was to compare MRI findings in unipolar patients with and without a history of attempted suicide. We applied the analysis of voxelbased morphometry (VBM) to structural T1-weighted images, and hypothesized that volume reductions in young suicidal depressed patients might implicate more brain regions than the classical frontolimbic networks, such as those in the temporal or parietal lobes.
each subject, an anatomical image was obtained using a sagittal three-dimensional gradient-echo T1-weighted sequence (TR¼7.6 ms, TED¼ 3.7 ms, TI¼ 795 ms, Flip angle¼81, 180 slices, slice thickness¼ 1 mm, Gap¼ 0 mm, matrix¼256 256, Inversion time¼0). For preventing the patients with suicide attempt to commit suicide again, the average interval between the scanning and the last suicide attempt in our study is about 4 weeks after medical intervention. 2.3. Image processing All T1-weighted MR images were analyzed using SPM8 (Wellcome Institute of Neurology, University College London, UK; http://www.fil.ion.ucl.ac.uk/spm). First, the “New Segmentation” algorithm from SPM8 was applied to each T1-weighted MR image to extract tissue maps corresponding to gray matter, white matter, and cerebrospinal fluid (CSF). Next, all segmented tissue maps were used to create a customized, population specific template using the DARTEL template-creation tool (Ashburner, 2007). At the end of the process, each subject's gray matter map was warped using its corresponding smooth, reversible deformation parameters to the custom template space, and then to the MNI standard space. All warped gray matter images were then modulated by calculating the Jacobian determinants derived from the special normalization step and multiplying each voxel by the relative change in volume (Good et al., 2001). Finally, all wrapped modulated gray matter images were smoothed with an 8-mm Gaussian kernel before voxel-wise group comparisons. 2.4. Statistical analysis
2. Materials and methods 2.1. Subjects 38 depressed patients between the ages of 18 and 45 years were recruited from the inpatient and outpatient units at Guangzhou Psychiatric Hospital, Affiliated Hospital of Guangzhou Medical University, in which 20 depressed patients had more than one time of suicide behaviors. The structured clinical interview (SCID) for DSM-IV diagnostic criteria was used to assess the presence or absence of major depressive disorder (MDD). Any patient with other psychiatric axis-I or axis-II disorders, any other neurological disorder, any substance use within the past 6 months, electroconvulsive therapy, any kind of contraindication for magnetic resonance imaging (MRI), and any other clinically relevant abnormalities in their medical history or laboratory examinations was excluded. The suicidal and non-suicidal depressed groups were all mainly treated by the antidepressants of selective serotonin reuptake inhibitors (SSRIs); there were no significant differences in the types and dosage of medicine between these two depressive groups. A 17-item Hamilton Depressive Rating Scale (HAMD) (Hamilton, 1960) and Zung's SelfRating Depression Scale (SDS) were used to evaluate depression severity; the Dysfunctional Attitudes Scale (DAS) (Weissman and Beck, 1978) was used to measure cognitive scheme in depressed patients. In addition, 28 sex- and age-matched healthy controls were recruited from the local community. Before enrollment, all subjects were fully informed of the details of the study and written informed consent was obtained. These studies were performed according to the Declaration of Helsinki and approved by the Guangzhou Psychiatric Hospital Ethics Committee.
One-way ANOVAs were used to test the group differences in clinical and demographic characteristics of all subjects using SPSS17.0 software. Post-hoc pairwise comparisons were then performed using t tests. Smoothed modulated gray matter images were analyzed with SPM8 utilizing the framework of General Linear Model (GLM). Voxel-wise gray matter volume differences among three groups were investigated using Analysis of variance (ANOVA) model. Post-hoc pairwise comparisons were used to compare differences in gray matter volume between any two groups. The covariates included in the model were total gray matter volume (TGMV) calculated from modulated gray matter images, age, gender, and education years. An initial threshold of 50 voxels or greater, surviving a false discovery rate (FDR) threshold of po0.05, was set (Genovese et al., 2002). Moreover, we performed a region-of-interest (ROI) analysis of regional gray matter volume (RGMV), in which the ROIs were defined as the significant brain areas found in the voxel-wise analysis of gray matter volume. The partial correlation between the clinical data and the RGMV of each ROI was calculated, controlling for the age, gender, education years, and TGMV. 2.5. Dysfunctional attitude evaluation The Dysfunctional Attitudes Scale (DAS) is a 40-item questionnaire designed to measure cognitive vulnerability to depression, which may reflect the impact of early negative events on one's cognition about self and the world. Higher scores reflect more dysfunctional attitudes.
3. Results
2.2. Image acquisition
3.1. Clinical and demographic characteristics of the subjects
Structural MRI scans were acquired using Philips 3 T MR systems (Philips, Best, The Netherlands) located at Guangzhou Psychiatric Hospital, Affiliated Hospital of Guangzhou Medical University. For
Analysis of variance showed that there was no significant difference in age, gender, marriage state among the three groups: 20 depressed patients with suicide history, 18 depressed patients
H. Peng et al. / Journal of Affective Disorders 165 (2014) 69–73
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Table 1 Clinical and demographic characteristics among healthy controls, depressed patients with and without suicide attempt. Variable
HC (n¼ 28) Mean
Age (y) Gender (male/female) (n) Education (years) marriage (single/married) (n) Course (months) HAMD SDS DAS
SD
28.61 15/13 15.42 17/11
5.45 3.68
116.96
17.25
Depression with Sui (n¼ 20)
Depression without Sui (n¼ 18)
Mean
Mean
SD
27.75 7/13 13.24 10/10 21.46 25.95 55.05 154.05
7.21
SD
31.06 6/12 13.55 7/11 23.45 24.06 56.94 134.5
2.82 21.27 6.48 9.56 30.53
F/P value
7.39
0.281 0.400 0.469 0.236 0.581 0.221 0.429 0.000
3.22 20.14 1.83 4.21 16.55
HC¼ Healthy controls; SD ¼ Standard deviation; SDS ¼Self-Rating Depression scale; HAMD¼ Hamilton Depressive Rating Scale; Depression with Sui ¼ Depression with suicide attempt; Depression without Sui ¼Depression without suicide attempt.
Table 2 Gray matter volume comparison between depressed patients with and without suicide history and healthy controls. Anatomical region
G1–G2 G1–G3 G3–G1 G2–G3
Insula Middle temporal gyrus Parietal Limbic cingulate gyrus
Left/Right
L R R L
Voxel level P (FDR-corrected)
0.023 0.015 0.032 0.045
Size (voxels)
167 890 173 59
MNI (mm)
Voxel Z-value
x
y
z
35 60 39 2
18 53 39 21
9 8 60 28
2.98 3.43 3.33 2.78
G1 ¼ Healthy controls; G2 ¼Depression without suicide history; G3 ¼ Depression with suicide history. 50 voxels minimum extent, p o 0.05. FDR: false discovery rate; MNI: Montreal Neurological Institute.
without suicide history, and 28 healthy control subjects. There was no significant difference in disease course, HAMD scores, SDS scores between depressed patients with and without suicide attempt (p 40.05). The DAS scores were significantly different among the three groups (p o0.001, see Table 1), and the post-hoc analysis showed that there was a significant difference in DAS scores between patients with and without suicide history (p o0.05). 3.2. Different gray matter volumes between control group and depressed patients with and without suicidal history Compared with controls, patients without suicide history showed significant decreased gray matter volume in the left insula lobe [ 35 18 9], and patients with suicide history showed significantly decreased gray matter volume in the right middle temporal gyrus [60 53 8] and increased gray matter volume in the right parietal lobe [39 39 60]. Compared with the non-suicidal depressed patient group, the suicidal group showed significant decreased gray matter volume in the left limbic cingulated gyrus [ 2 21 28]. The three areas survived a FDR threshold of po0.05 at cluster level or voxel level (see Table 2 and Fig. 1). 3.3. The correlations between DAS scores and gray matter volume values in left limbic cingulate gyrus in suicidal depressed patients In this study, 20 depressed patients with suicide history were compared with 18 patients without suicide history. The resulting significant reduced brain region in the left limbic cingulate gyrus was defined region of interest (ROI). The corrected region of gray matter volume (cRGMV) of the ROI was adjusted by age, sex, educational years, and total gray matter volume (TGMV). The values of cRGMV were extracted, and the Pearson's correlation test (two-tailed) was performed between the DAS and the values of cRGMV of depressed subjects with suicide history, the results revealed negative correlations between cRGMV values and dysfunctional attitude scores (r ¼ 0.497, p¼ 0.026) (see Fig. 2).
4. Discussion In this study, we found that depressed patients had smaller gray matter volumes in the left insular lobe, consistent with previous studies. Several previous neuroimaging studies have indicated that the insular cortex is a neuroanatomical substrate for MDD (Sprengelmeyer et al., 2011). The insula, particularly the anterior division, is involved in disparate cognitive, affective, and regulatory functions in high-level cognitive control and attentional processes (Kurth et al., 2010; Menon and Uddin, 2010). The insula has an abundance of local intrainsular connections and projections to adjacent brain areas including the cingulate gyrus, amygdaloid nuclei and other brain regions related to emotion modulation (Augustine, 1996; Singer et al., 2009). The idea of the insula as the ‘limbic integration cortex’ is widely accepted and abnormal frontolimbic networks are considered substrates underlying MDD (Augustine, 1996; Menon and Uddin, 2010). Our study also demonstrated that patients with a history of attempted suicide had significantly smaller gray matter volumes in the right middle temporal gyrus and larger gray matter volumes in the right parietal lobe compared with matched healthy controls. These results suggested that the abnormal brain regions in patients who had attempted suicide included the parietal and temporal lobes. Previous studies suggested that suicidal behavior was associated with changes in the structural and functional characteristics of the parietal–occipital–temporal areas. A previous study has shown lower gray matter density in the left superior temporal gyrus, greater activity in the inferior parietal lobule, and greater tryptophan trapping in the left middle occipital cortex (van Heeringen et al., 2010). Another previous study has indicated significantly lower gray matter density in the left superior temporal lobe and left orbitofrontal cortex in patients with schizophrenia who had attempted suicide than in those who had not (Aguilar et al., 2008). In addition, the parietal lobe is considered to be purely an ‘association cortex’, a zone in which many related functions such as spatial representation, working memory, eye movements, and parietal functions such as attention may be particularly effective at producing activation (Aguilar et al., 2008).
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Fig. 1. Gray matter volume differences between depressed patients with and without suicide history and healthy controls. (a) left insula; (b) right middle temporal gyrus; (c) right parietal lobe; (d) left limbic cingulate gyrus. 50 voxels minimum extent, p o 0.05, false discovery rate corrected.
Fig. 2. Gray matter volume values in left limbic cingulated gyrus were negatively correlated with dysfunctional attitude scores in depressed subjects with suicide history (r¼ 0.497, p ¼0.026). cRGMV ¼ corrected regional gray matter volume in left limbic cingulate gyrus.
In addition, our comparison of suicidal and non-suicidal depressed patients revealed gray matter alteration in the left limbic cingulate gyrus. Our results were partly consistent with previous studies. For example, a previous study has indicated abnormal gray matter volumes in the caudate and rostral anterior cingulate cortex in suicidal depressed patients compared with non-suicidal depressed patients(Wagner et al., 2011). Other studies have shown abnormal gray matter volumes in anterior medial frontal regions, including the ventromedial, orbitofrontal, and anterior cingulate cortices, which are considered to play an important role in impulsive and suicidal behaviors (Desmyter et al., 2011; van Heeringen et al., 2010). Limbic gray matter hyperintensities are more commonly found in cases with a history of suicide attempt than without (Marchand et al., 2012; van Heeringen et al., 2010). Previous studies have shown that suicidal behavior in depression might be related to abnormal fronto-striato-limbic networks
(Wagner et al., 2011). For example, a previous study has indicated that patients at high risk for suicide had significantly lower gray matter densities in the fronto-striato-limbic network than matched healthy controls (Wagner et al., 2011). We found that abnormal gray matter volume brain regions related to suicidal behaviors affected regions outside the fronto-striato-limbic networks, and that temporal–parietal–limbic networks were also involved in young depressed patients with a history of attempted suicide. Finally, we also found that gray matter volumes in the left limbic cingulate gyrus correlated negatively with dysfunctional attitude scores in depressed patients. A dysfunctional attitude reflects cognition about oneself and the world, and is usually affected by life events such as childhood trauma (Bower and Sivers, 1998; Ingram et al., 1998; Scher et al., 2005). Distorted cognition often leads to negative beliefs and behaviors, which may include suicide in adulthood. Previous studies have consistently shown that suicidal behaviors are related to three cognitive characteristics: (1) an attentional bias to particular life events reflecting signals of defeat (‘loser’ status), (2) the insufficient capacity to solve problems, (3) hopelessness; the neural basis of these characteristics is thought to be related to an impairment of the neural networks for cognition and emotion (Beck, 1979; Brown et al., 2005; Patsiokas et al., 1979). The cingulate cortex receives inputs from the thalamus and the neocortex, and projects to the entorhinal cortex via the cingulum. It is an integral part of the limbic system, which is involved with emotion formation and processing and cognitive function such as learning and memory (Hadland et al., 2003). Our results supported the relationship between dysfunctional cognition and abnormal gray matter volumes in the cingulate cortex in young depressed patients with a history of attempted suicide. Limitation: Our results required replication and further clarification in a larger patient population. Surprisingly, we did not observe classical changes in the fronto-striato-limbic networks, which might be due to the small sample size. Volumetric
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brain analysis as an exploratory method is helpful in discovering unexpected or unpredicted neuroanatomical areas, but can lead to false positives. More factors (including family history of suicide, numbers of suicide, medication load) should be controlled in future study because these factors may also be associated with brain structural changes. In addition, a more powerful correction should be applied; our small sample size limited the correction. In conclusion, suicide attempts in young depressed patients may be related to abnormal gray matter volume in temporal– parietal–limbic networks. Volumetric decrease in the left limbic cingulate gyrus may be a candidate for the prediction of suicide in young depressed people.
Role of funding source This study was supported by the National Natural Science Foundation of China (C090104 to Yuping Ning); the Medical Research Foundation of Guangdong, China (A2012523 to Hongjun Peng); the Science and Technology Program of Guangzhou, China (2010Y1-C631 to Yuping Ning and 2013J4100096 to Hongjun Peng); the National Clinical Key Special Program, China (201201003 to Hongjun Peng); the Guangdong Natural Science Foundation, China (S2012040007743 to Kai Wu); the Fundamental Research Funds of Central Universities under the South China University of Technology, China (2013ZM046 to Kai Wu); the Guangzhou municipal key discipline in medicine for Guangzhou Brain Hospital (GBH2014-ZD04 to Hongjun Peng).
Conflict of interest All authors declare that they have no conflict of interest.
Acknowledgment We thank our subjects for their readiness to engage in this study, and the experts at the Magnetic Resonance Room of Guangzhou Psychiatric Hospital, Affiliated Hospital of Guangzhou Medical University for providing scan time and technical assistant.
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Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Increased suicide attempts in young depressed patients with abnormal temporal–parietal–limbic gray matter volume Hongjun Peng a,n,1, Kai Wu b,nn, Jie Li a, Haochen Qi b, Shengwen Guo b, Minyue Chi b, Xiaoming Wu b, Yangbo Guo a, Yuling Yang a, Yuping Ning a,1 a b
Guangzhou Psychiatric Hospital, Affiliated Hospital of Guangzhou Medical University, Guangzhou, China Department of Biomedical Engineering, School of Materials Science and Engineering, South China University of Technology, Guangzhou, China
art ic l e i nf o
a b s t r a c t
Article history: Received 30 November 2013 Received in revised form 18 March 2014 Accepted 17 April 2014 Available online 24 April 2014
Background: Suicide is a major cause of death throughout the world. Approximately 60% of all suicides have a history of depression. Previous studies of structural brain imaging have shown that suicide is often associated with abnormal fronto-limbic networks. However, the mechanism underlying suicide in depression remains poorly understood. Method: Twenty sex- and age-matched suicidal unipolar patients were compared with 18 non-suicidal unipolar patients and 28 healthy controls. High-resolution T1-weighted 3 T magnetic resonance imaging (MRI) scans were acquired. Hamilton Depressive Rating Scale (HAMD) and Self-Rating Depression scale (SDS) were evaluated. The criterion for suicidality was one or more documented lifetime suicide attempts. A whole-brain optimized voxel-based morphometry (VBM) approach was applied. The Dysfunctional Attitude Scale (DAS) was used to measure cognitive scheme in depressive patients. Results: Compared with controls, patients without suicide history showed significant decreased gray matter volume in the left insula lobe [ 35 18 9], whereas patients with suicide history showed significantly decreased gray matter volume in the right middle temporal gyrus [60 53 8] and increased gray matter volume in the right parietal lobe [39 39 60]. Compared with the non-suicidal depressed patient group, the suicidal group showed significant decreased gray matter volume in left limbic cingulated gyrus [ 2 21 28]. Moreover, the gray matter volume values in this significantly different brain region were negatively correlated with dysfunctional attitude scores in suicidal depressed patients. Limitations: This study needs replication and further clarification in a larger patient population. Conclusions: Suicide attempts in young depressed patients may be related to abnormal gray matter volumes in temporal–parietal–limbic networks. Specifically, small left limbic cingulate gyrus volumes may be a candidate for the prediction of suicide in young depressed patients. & 2014 Elsevier B.V. All rights reserved.
Keywords: Depression Voxel based morphometry (VBM) Gray matter volume Suicide attempt
1. Introduction Suicide is a major cause of death throughout the world and is becoming a significant public health issue. Approximately 15 per
Abbreviations: ACC, Anterior cingulate cortex; ANOVA, Analysis of variance; CSF, Cerebrospinal fluid; DAS, Dysfunctional Attitudes Scale; FDR, False discovery rate; GLM, General Linear Model; GM, Gray matter; HAMD, Hamilton Depressive Rating Scale; LOD, Late onset depression; MDD, Major depression disorder; MRI, Magnetic resonance imaging; PFC, Prefrontal cortex; RGMV, Analysis of regional gray matter volume; ROI, Region-of-interest; SCID, Structured clinical interview; SDS, SelfRating Depression scale; SSRIs, Selective serotonin reuptake inhibitors; VBM, Voxel based morphometry. n Corresponding author. Tel.: þ 86 20 81268184; fax: þ 86 20 81891391. nn Corresponding author. Tel.: þ 86 20 3938 0660. E-mail addresses: [email protected] (H. Peng), [email protected] (K. Wu). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.jad.2014.04.046 0165-0327/& 2014 Elsevier B.V. All rights reserved.
100,000 individuals commit suicide each year, and 10–20 times more engage in non-fatal suicidal behavior (Kerkhof, 2000; Krug et al., 2002; van Heeringen et al., 2010). Sixty per cent of people who commit suicide have a history of depressive disorder (Carlson et al., 1991; Lee and Kim, 2011). The mechanism underlying suicide in depression remains unclear. Preclinical studies using animal models, and neuroendocrine and neurobiological studies of suicide cases, have mainly focused on the serotonin system (Mann et al., 2000; Owen et al., 1986; Stoff and Mann, 1997). Recent advances in magnetic resonance imaging (MRI) techniques have provided a noninvasive method by which to explore the cause of suicide in vivo. Structural brain imaging studies in suicidal patients with major depressive disorder (MDD) have found abnormal gray matter volumes or densities in suicide attempters; in particular, smaller volumes of the hippocampus, dorsolateral prefrontal cortex,
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orbitofrontal cortex, anterior cingulate, superior temporal cortex, parieto-occipital cortex, and basal ganglia (Ahearn et al., 2001; Desmyter et al., 2010; Hwang et al., 2010; Mann, 2005; Marchand et al., 2012; Monkul et al., 2007; Wagner et al., 2011). A previous study showed that long-term lithium treatment could improve gray matter volume deficit in suicidal patients (Benedetti et al., 2011). Previous studies have mainly focused on late onset depression (LOD; defined as onset over age 50) or elderly patients with MDD, and suggested that the total volume of frontal lobe in patients may be smaller than that in healthy controls (Figiel et al., 1991; Howard et al., 1993; Pompili et al., 2010). Subcortical gray matter hyperintensities have also been noted in the basal ganglia of LOD patients (Iidaka et al., 1996; Steffens et al., 1999). In addition, atrophy often occurs in the basal nuclei, cerebellum, and brainstem in elderly patients with depression. To our knowledge, very few studies have explored the changes in gray matter in young suicidal depressed patients, and few previous studies have found abnormal gray matter volumes in the temporal or parietal lobes in suicidal psychiatric patients (Aguilar et al., 2008; van Heeringen et al., 2010). Therefore, the purpose of the present study was to compare MRI findings in unipolar patients with and without a history of attempted suicide. We applied the analysis of voxelbased morphometry (VBM) to structural T1-weighted images, and hypothesized that volume reductions in young suicidal depressed patients might implicate more brain regions than the classical frontolimbic networks, such as those in the temporal or parietal lobes.
each subject, an anatomical image was obtained using a sagittal three-dimensional gradient-echo T1-weighted sequence (TR¼7.6 ms, TED¼ 3.7 ms, TI¼ 795 ms, Flip angle¼81, 180 slices, slice thickness¼ 1 mm, Gap¼ 0 mm, matrix¼256 256, Inversion time¼0). For preventing the patients with suicide attempt to commit suicide again, the average interval between the scanning and the last suicide attempt in our study is about 4 weeks after medical intervention. 2.3. Image processing All T1-weighted MR images were analyzed using SPM8 (Wellcome Institute of Neurology, University College London, UK; http://www.fil.ion.ucl.ac.uk/spm). First, the “New Segmentation” algorithm from SPM8 was applied to each T1-weighted MR image to extract tissue maps corresponding to gray matter, white matter, and cerebrospinal fluid (CSF). Next, all segmented tissue maps were used to create a customized, population specific template using the DARTEL template-creation tool (Ashburner, 2007). At the end of the process, each subject's gray matter map was warped using its corresponding smooth, reversible deformation parameters to the custom template space, and then to the MNI standard space. All warped gray matter images were then modulated by calculating the Jacobian determinants derived from the special normalization step and multiplying each voxel by the relative change in volume (Good et al., 2001). Finally, all wrapped modulated gray matter images were smoothed with an 8-mm Gaussian kernel before voxel-wise group comparisons. 2.4. Statistical analysis
2. Materials and methods 2.1. Subjects 38 depressed patients between the ages of 18 and 45 years were recruited from the inpatient and outpatient units at Guangzhou Psychiatric Hospital, Affiliated Hospital of Guangzhou Medical University, in which 20 depressed patients had more than one time of suicide behaviors. The structured clinical interview (SCID) for DSM-IV diagnostic criteria was used to assess the presence or absence of major depressive disorder (MDD). Any patient with other psychiatric axis-I or axis-II disorders, any other neurological disorder, any substance use within the past 6 months, electroconvulsive therapy, any kind of contraindication for magnetic resonance imaging (MRI), and any other clinically relevant abnormalities in their medical history or laboratory examinations was excluded. The suicidal and non-suicidal depressed groups were all mainly treated by the antidepressants of selective serotonin reuptake inhibitors (SSRIs); there were no significant differences in the types and dosage of medicine between these two depressive groups. A 17-item Hamilton Depressive Rating Scale (HAMD) (Hamilton, 1960) and Zung's SelfRating Depression Scale (SDS) were used to evaluate depression severity; the Dysfunctional Attitudes Scale (DAS) (Weissman and Beck, 1978) was used to measure cognitive scheme in depressed patients. In addition, 28 sex- and age-matched healthy controls were recruited from the local community. Before enrollment, all subjects were fully informed of the details of the study and written informed consent was obtained. These studies were performed according to the Declaration of Helsinki and approved by the Guangzhou Psychiatric Hospital Ethics Committee.
One-way ANOVAs were used to test the group differences in clinical and demographic characteristics of all subjects using SPSS17.0 software. Post-hoc pairwise comparisons were then performed using t tests. Smoothed modulated gray matter images were analyzed with SPM8 utilizing the framework of General Linear Model (GLM). Voxel-wise gray matter volume differences among three groups were investigated using Analysis of variance (ANOVA) model. Post-hoc pairwise comparisons were used to compare differences in gray matter volume between any two groups. The covariates included in the model were total gray matter volume (TGMV) calculated from modulated gray matter images, age, gender, and education years. An initial threshold of 50 voxels or greater, surviving a false discovery rate (FDR) threshold of po0.05, was set (Genovese et al., 2002). Moreover, we performed a region-of-interest (ROI) analysis of regional gray matter volume (RGMV), in which the ROIs were defined as the significant brain areas found in the voxel-wise analysis of gray matter volume. The partial correlation between the clinical data and the RGMV of each ROI was calculated, controlling for the age, gender, education years, and TGMV. 2.5. Dysfunctional attitude evaluation The Dysfunctional Attitudes Scale (DAS) is a 40-item questionnaire designed to measure cognitive vulnerability to depression, which may reflect the impact of early negative events on one's cognition about self and the world. Higher scores reflect more dysfunctional attitudes.
3. Results
2.2. Image acquisition
3.1. Clinical and demographic characteristics of the subjects
Structural MRI scans were acquired using Philips 3 T MR systems (Philips, Best, The Netherlands) located at Guangzhou Psychiatric Hospital, Affiliated Hospital of Guangzhou Medical University. For
Analysis of variance showed that there was no significant difference in age, gender, marriage state among the three groups: 20 depressed patients with suicide history, 18 depressed patients
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Table 1 Clinical and demographic characteristics among healthy controls, depressed patients with and without suicide attempt. Variable
HC (n¼ 28) Mean
Age (y) Gender (male/female) (n) Education (years) marriage (single/married) (n) Course (months) HAMD SDS DAS
SD
28.61 15/13 15.42 17/11
5.45 3.68
116.96
17.25
Depression with Sui (n¼ 20)
Depression without Sui (n¼ 18)
Mean
Mean
SD
27.75 7/13 13.24 10/10 21.46 25.95 55.05 154.05
7.21
SD
31.06 6/12 13.55 7/11 23.45 24.06 56.94 134.5
2.82 21.27 6.48 9.56 30.53
F/P value
7.39
0.281 0.400 0.469 0.236 0.581 0.221 0.429 0.000
3.22 20.14 1.83 4.21 16.55
HC¼ Healthy controls; SD ¼ Standard deviation; SDS ¼Self-Rating Depression scale; HAMD¼ Hamilton Depressive Rating Scale; Depression with Sui ¼ Depression with suicide attempt; Depression without Sui ¼Depression without suicide attempt.
Table 2 Gray matter volume comparison between depressed patients with and without suicide history and healthy controls. Anatomical region
G1–G2 G1–G3 G3–G1 G2–G3
Insula Middle temporal gyrus Parietal Limbic cingulate gyrus
Left/Right
L R R L
Voxel level P (FDR-corrected)
0.023 0.015 0.032 0.045
Size (voxels)
167 890 173 59
MNI (mm)
Voxel Z-value
x
y
z
35 60 39 2
18 53 39 21
9 8 60 28
2.98 3.43 3.33 2.78
G1 ¼ Healthy controls; G2 ¼Depression without suicide history; G3 ¼ Depression with suicide history. 50 voxels minimum extent, p o 0.05. FDR: false discovery rate; MNI: Montreal Neurological Institute.
without suicide history, and 28 healthy control subjects. There was no significant difference in disease course, HAMD scores, SDS scores between depressed patients with and without suicide attempt (p 40.05). The DAS scores were significantly different among the three groups (p o0.001, see Table 1), and the post-hoc analysis showed that there was a significant difference in DAS scores between patients with and without suicide history (p o0.05). 3.2. Different gray matter volumes between control group and depressed patients with and without suicidal history Compared with controls, patients without suicide history showed significant decreased gray matter volume in the left insula lobe [ 35 18 9], and patients with suicide history showed significantly decreased gray matter volume in the right middle temporal gyrus [60 53 8] and increased gray matter volume in the right parietal lobe [39 39 60]. Compared with the non-suicidal depressed patient group, the suicidal group showed significant decreased gray matter volume in the left limbic cingulated gyrus [ 2 21 28]. The three areas survived a FDR threshold of po0.05 at cluster level or voxel level (see Table 2 and Fig. 1). 3.3. The correlations between DAS scores and gray matter volume values in left limbic cingulate gyrus in suicidal depressed patients In this study, 20 depressed patients with suicide history were compared with 18 patients without suicide history. The resulting significant reduced brain region in the left limbic cingulate gyrus was defined region of interest (ROI). The corrected region of gray matter volume (cRGMV) of the ROI was adjusted by age, sex, educational years, and total gray matter volume (TGMV). The values of cRGMV were extracted, and the Pearson's correlation test (two-tailed) was performed between the DAS and the values of cRGMV of depressed subjects with suicide history, the results revealed negative correlations between cRGMV values and dysfunctional attitude scores (r ¼ 0.497, p¼ 0.026) (see Fig. 2).
4. Discussion In this study, we found that depressed patients had smaller gray matter volumes in the left insular lobe, consistent with previous studies. Several previous neuroimaging studies have indicated that the insular cortex is a neuroanatomical substrate for MDD (Sprengelmeyer et al., 2011). The insula, particularly the anterior division, is involved in disparate cognitive, affective, and regulatory functions in high-level cognitive control and attentional processes (Kurth et al., 2010; Menon and Uddin, 2010). The insula has an abundance of local intrainsular connections and projections to adjacent brain areas including the cingulate gyrus, amygdaloid nuclei and other brain regions related to emotion modulation (Augustine, 1996; Singer et al., 2009). The idea of the insula as the ‘limbic integration cortex’ is widely accepted and abnormal frontolimbic networks are considered substrates underlying MDD (Augustine, 1996; Menon and Uddin, 2010). Our study also demonstrated that patients with a history of attempted suicide had significantly smaller gray matter volumes in the right middle temporal gyrus and larger gray matter volumes in the right parietal lobe compared with matched healthy controls. These results suggested that the abnormal brain regions in patients who had attempted suicide included the parietal and temporal lobes. Previous studies suggested that suicidal behavior was associated with changes in the structural and functional characteristics of the parietal–occipital–temporal areas. A previous study has shown lower gray matter density in the left superior temporal gyrus, greater activity in the inferior parietal lobule, and greater tryptophan trapping in the left middle occipital cortex (van Heeringen et al., 2010). Another previous study has indicated significantly lower gray matter density in the left superior temporal lobe and left orbitofrontal cortex in patients with schizophrenia who had attempted suicide than in those who had not (Aguilar et al., 2008). In addition, the parietal lobe is considered to be purely an ‘association cortex’, a zone in which many related functions such as spatial representation, working memory, eye movements, and parietal functions such as attention may be particularly effective at producing activation (Aguilar et al., 2008).
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Fig. 1. Gray matter volume differences between depressed patients with and without suicide history and healthy controls. (a) left insula; (b) right middle temporal gyrus; (c) right parietal lobe; (d) left limbic cingulate gyrus. 50 voxels minimum extent, p o 0.05, false discovery rate corrected.
Fig. 2. Gray matter volume values in left limbic cingulated gyrus were negatively correlated with dysfunctional attitude scores in depressed subjects with suicide history (r¼ 0.497, p ¼0.026). cRGMV ¼ corrected regional gray matter volume in left limbic cingulate gyrus.
In addition, our comparison of suicidal and non-suicidal depressed patients revealed gray matter alteration in the left limbic cingulate gyrus. Our results were partly consistent with previous studies. For example, a previous study has indicated abnormal gray matter volumes in the caudate and rostral anterior cingulate cortex in suicidal depressed patients compared with non-suicidal depressed patients(Wagner et al., 2011). Other studies have shown abnormal gray matter volumes in anterior medial frontal regions, including the ventromedial, orbitofrontal, and anterior cingulate cortices, which are considered to play an important role in impulsive and suicidal behaviors (Desmyter et al., 2011; van Heeringen et al., 2010). Limbic gray matter hyperintensities are more commonly found in cases with a history of suicide attempt than without (Marchand et al., 2012; van Heeringen et al., 2010). Previous studies have shown that suicidal behavior in depression might be related to abnormal fronto-striato-limbic networks
(Wagner et al., 2011). For example, a previous study has indicated that patients at high risk for suicide had significantly lower gray matter densities in the fronto-striato-limbic network than matched healthy controls (Wagner et al., 2011). We found that abnormal gray matter volume brain regions related to suicidal behaviors affected regions outside the fronto-striato-limbic networks, and that temporal–parietal–limbic networks were also involved in young depressed patients with a history of attempted suicide. Finally, we also found that gray matter volumes in the left limbic cingulate gyrus correlated negatively with dysfunctional attitude scores in depressed patients. A dysfunctional attitude reflects cognition about oneself and the world, and is usually affected by life events such as childhood trauma (Bower and Sivers, 1998; Ingram et al., 1998; Scher et al., 2005). Distorted cognition often leads to negative beliefs and behaviors, which may include suicide in adulthood. Previous studies have consistently shown that suicidal behaviors are related to three cognitive characteristics: (1) an attentional bias to particular life events reflecting signals of defeat (‘loser’ status), (2) the insufficient capacity to solve problems, (3) hopelessness; the neural basis of these characteristics is thought to be related to an impairment of the neural networks for cognition and emotion (Beck, 1979; Brown et al., 2005; Patsiokas et al., 1979). The cingulate cortex receives inputs from the thalamus and the neocortex, and projects to the entorhinal cortex via the cingulum. It is an integral part of the limbic system, which is involved with emotion formation and processing and cognitive function such as learning and memory (Hadland et al., 2003). Our results supported the relationship between dysfunctional cognition and abnormal gray matter volumes in the cingulate cortex in young depressed patients with a history of attempted suicide. Limitation: Our results required replication and further clarification in a larger patient population. Surprisingly, we did not observe classical changes in the fronto-striato-limbic networks, which might be due to the small sample size. Volumetric
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brain analysis as an exploratory method is helpful in discovering unexpected or unpredicted neuroanatomical areas, but can lead to false positives. More factors (including family history of suicide, numbers of suicide, medication load) should be controlled in future study because these factors may also be associated with brain structural changes. In addition, a more powerful correction should be applied; our small sample size limited the correction. In conclusion, suicide attempts in young depressed patients may be related to abnormal gray matter volume in temporal– parietal–limbic networks. Volumetric decrease in the left limbic cingulate gyrus may be a candidate for the prediction of suicide in young depressed people.
Role of funding source This study was supported by the National Natural Science Foundation of China (C090104 to Yuping Ning); the Medical Research Foundation of Guangdong, China (A2012523 to Hongjun Peng); the Science and Technology Program of Guangzhou, China (2010Y1-C631 to Yuping Ning and 2013J4100096 to Hongjun Peng); the National Clinical Key Special Program, China (201201003 to Hongjun Peng); the Guangdong Natural Science Foundation, China (S2012040007743 to Kai Wu); the Fundamental Research Funds of Central Universities under the South China University of Technology, China (2013ZM046 to Kai Wu); the Guangzhou municipal key discipline in medicine for Guangzhou Brain Hospital (GBH2014-ZD04 to Hongjun Peng).
Conflict of interest All authors declare that they have no conflict of interest.
Acknowledgment We thank our subjects for their readiness to engage in this study, and the experts at the Magnetic Resonance Room of Guangzhou Psychiatric Hospital, Affiliated Hospital of Guangzhou Medical University for providing scan time and technical assistant.
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