Association of Suicidal Status, Inflammation Markers and Resting State Functional Connectivity in Patients with Major Depressive Disorder

doi:10.21203/rs.3.rs-2669073/v1

Suicidal ideation and attempt might have distinct neural underpinnings. Identifying the neural substrates of suicide behaviors might help to reduce suicide rates. This study wanted to identify i) neural markers of suicide attempt using resting-state functional magnetic resonance imaging (rs-fMRI), and ii) associations between rs-fMRI metrics, suicidal phenotype and peripheral blood inflammation markers. We measured inflammation markers [C-reactive protein (CRP), interleukin (IL)-1b, IL-2, IL-6, TNF-a) and rs-fMRI metrics in 20 healthy controls (HCs) and 42 patients with unipolar depression [n=21 suicide attempters (SAs) in the last 8 days and n=21 affective controls (ACs) without lifetime history of suicide]. Amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo) and Voxel-Mirrored Homotopic Connectivity (VMHC) were estimated in prefrontal cortex, anterior cingulate cortex and insula. Participants were mainly women (66.7% of HCs, 71.4% of ACs and 85% of SAs; age range 40 to 48 years). CRP (but not IL) concentration was higher in SAs than ACs and HCs. ALFF values were decreased in the pars opercularis of the inferior frontal gyrus in SAs vs. ACs and HCs, even after controlling for suicidal ideation intensity and CRP level. Suicidal ideation intensity was negatively correlated with all rs-fMRI metrics (except ReHo of left side) of this region in SAs and ACs. Inflammation markers were not correlated with the rs-fMRI metrics. Resting-state dysfunctional connectivity in regions involved in language and cognitive control is associated with suicide intensity and attempts, but not with inflammation markers.

Health sciences/Diseases/Psychiatric disorders/Depression

Health sciences/Biomarkers/Diagnostic markers

Suicide represents a major health problem worldwide. Transnosographic features suggest that suicidal behavior has its own physiopathology and should be considered a specific clinical entity. Indeed, according to the DSM-5, suicidal behavior could be a separate diagnosis ¹, emphasizing the relevance of identifying specific biomarkers ².

Identifying the neural substrates of suicide attempt is key to understanding suicide etiology and might help to reduce suicide rates among psychiatric patients by promoting the development of novel therapeutic strategies based on behavioral neuroscience and brain stimulation. Neuroimaging studies have shown structural and functional brain abnormalities in the prefrontal cortex, insula and striatal regions and also in the connections between these brain areas ³. Disturbances in the structure and function of brain regions can lead to brain network alterations, including the ability of brain regions to coordinate their activity in a system. Resting-state functional magnetic resonance imaging (rs-fMRI) studies have been used to explore the intrinsic activity or resting-state brain networks. As rs-fMRI does not require the patient’s collaboration, this increases its inter- and intra-individual reproducibility ⁴. In their review, Serafini et al., (2016) showed that vulnerability to suicidal behavior might be associated with abnormalities of the fronto-limbic and frontoparietal-cerebellar pathways and with negative blood oxygenation level-dependent responses in the anterior regions of the default mode network. However, differences in acquisition/analysis methods and in population characteristics among studies limit the finding interpretability. For instance, “suicidality” has been operationalized differently among studies (e.g., suicidal ideation, history of suicide attempts, or composite assessment) ^6,7. Some studies have focused on adolescents ^6,8–10 and others have included adults ^11–15.

To our knowledge, few studies have investigated the rs-fMRI activity in adult suicide attempters (SAs) with major depressive disorder (MDD). Compared with depressed controls, depressed SAs showed higher functional connectivity of the left amygdala-right insula/left superior orbitofrontal area and right amygdala-left middle temporal area ¹³. Such enhanced connectivity in limbic regions may contribute to emotional dysregulation. Moreover, the functional network connectivity between insular-default mode network and insular-cerebellum was decreased in patients with history of suicide attempt, reflecting impaired internal processing ¹². In addition, amplitude of low-frequency fluctuation (ALFF) values were significantly higher in the right superior and left middle temporal and occipital regions and significantly lower in the left superior and middle frontal gyri in SAs than in controls with depression ^8,16. Lastly, regional homogeneity (ReHo) in the right posterior cingulate cortex was increased in SAs with depression comparison with non-attempters ¹⁷.

Evidence converges towards distinct neural underpinnings between suicidal ideation and attempt ^18,19. In agreement, connectivity patterns between cognitive control network and salience and default mode networks were different in SAs and suicide ideators ¹⁸. Decreased ALFF values in a frontoparietal network and increased ALFF values in hippocampus distinguished SAs from suicide ideators, psychiatric and healthy controls (HCs) ¹⁹. However, these last two studies assessed suicidal ideation using one single item of the Diagnostic Interview for Genetic Studies and Hamilton Depression Rating Scale, respectively, instead of a validated scale for suicidal ideation and may have included suicidal ideators among SAs with depression. It would be interesting to correlate rs-fMRI metrics with the suicidal ideation intensity as a continuous dimension.

Lastly, growing evidence suggests the involvement of inflammation in mood disorders and in suicidal behaviors ²⁰. For instance, baseline blood levels of C-reactive protein (CRP) were higher in patients with history of suicide attempt than in depressed non-attempters, independently of the interval after the suicide attempt ²¹. Two meta-analyses reported that the blood concentrations of the pro-inflammatory cytokines interleukin (IL)-1β and IL-6 are significantly increased and those of the anti-inflammatory IL-2 are decreased in suicidal patients compared with non-suicidal patients and HCs ^22,23. Interestingly, CRP basal level has been associated with resting state functional connectivity in the default mode network, including in the ventromedial prefrontal cortex ^24–26, that in turn was correlated with anhedonia severity in patients with MDD ²⁵. Moreover, IL-6 covaried with connectivity of the medial prefrontal cortex in HCs ²⁷ and in patients with bipolar disorder ²⁸. However, data on associations between cytokines and rs-fMRI metrics in patients with MDD are still lacking.

Therefore, the aims of this study were i) to identify neural markers of suicide attempt in adults with MDD (and in HCs) using rs-fMRI, and ii) to find possible associations between rs-fMRI metrics, suicidal phenotype (level of suicidal ideation, lethality and suicidal intent of the last suicide attempt) and peripheral inflammation markers in patients with MDD.

Participants

The study sample included 20 HCs (individuals without any history of psychiatric disorders according to the DSM-5 criteria and no lifetime history of suicide attempt) and 42 patients with MDD [21 SAs with history of suicide attempt within the last 8 days, and 21 affective controls (ACs) without lifetime history of suicide attempt].

HCs were recruited through advertisement. Patients (SAs and ACs) were recruited among the inpatients of the Department of Emergency Psychiatry and Acute Care, Montpellier Academic Hospital, France. All participants were right-handed, Caucasian adults aged between 18 and 70 years. All patients (ACs and SAs) had a current depressive episode according to the DSM-5 criteria. Exclusion criteria were: current neurologic or inflammatory disease; CRP >10mg/L; current antibiotic or anti-inflammatory treatment; history of head trauma with loss of consciousness; current substance misuse, excluding tobacco; lifetime history of manic or hypomanic episode, schizophrenia, or schizoaffective disorder according to the DSM-5; pregnancy and breastfeeding; contraindication to MRI.

The study was conducted in accordance with the CONSORT ethical guidelines. All participants gave their written informed consent. The study was approved by Montpellier University Hospital (CPP Sud Méditerranée IV) ethics committee (N°ID-RCB : 2016-01267-44 (CPP Sud Méditerranée IV) and registered as NCT03052855 in clinicaltrial.gov. Participants in the study received a financial compensation of 50 euros.

Clinical assessment

Participants underwent a standardized interview led by a psychiatrist to determine the depression score and to assess psychopathology according to the DSM-5 criteria using the Mini-International Neuropsychiatric Interview, version 7.0.0. Depressive symptomatology was assessed using the clinician-rated Inventory of Depressive Symptomatology (IDSC-30) ²⁹. Current psychological pain was assessed using a 10-point Likert scale ³⁰. Suicidal ideation severity and intensity in the week before inclusion were assessed with the Columbia–Suicide Severity Rating Scale (C-SSRS) ³¹, and suicidal intent with the Suicidal Intent Scale (SIS) ³². The number of past suicide attempts and the lethality of the last attempt were recorded. All psychotropic treatments (name, daily dose) in the last 24 hours before MRI were recorded. The medication load was calculated for each patient according to ³³.

Laboratory analyses

Blood samples were collected after overnight fasting, between 7:00 and 9:00 AM, the day after admission, in 5 ml EDTA-coated tubes (BD Vacutainer, Franklin Lakes, NJ). High sensitivity CRP in serum was measured with the immunoturbidimetric method and a Cobas8000 modular analyzer (Roche Diagnostic, Meylan, France). Reagents and calibrators were used according to the manufacturer’s guidelines with analytic measuring ranges set at 0.3–350 mg/L.

Plasma was separated by centrifugation at 3000×g at room temperature for 20 minutes, and stored at -80°C for batch analysis by multiplex or ELISA assay of IL-1b, IL-6, IL-2, and tumor necrosis factor alpha (TNF-a). Analytes with >30% missing data were excluded from the analysis (IL-1b, IL-2).

Brain MRI

Brain MRI was performed using a 3T MRI scanner with a 32-channel head coil (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany) at the I2FH facility of Montpellier university hospital.
A high-resolution 3DT1 magnetization-prepared rapid gradient-echo (MPRAGE) sequence was acquired with the following parameters: repetition time (TR)/echo time (TE) = 2300/2.900ms, time of inversion = 900 ms, flip angle = 9°, voxel size = 1.2 x1 x1 mm³, and 176 sagittal slices. During rs-fMRI gradient echo-echo planar image acquisition (TR/TE = 3000/30 ms, flip angle = 80°, voxel size= 3.4 x 3.4 x 3.4 mm³, 42 transverse slices, 200 volumes measures, acquisition time = 10 min), participants were instructed to keep the eyes closed, lay still, and not to think about anything in particular.

MRI data preprocessing

Imaging data were preprocessed using MATLAB (TheMathworks Inc., MA) and SPM12 (http://www.fil.ion.ucl.ac.uk/spm/software/spm12/). All images were reoriented using the anterior commissure as reference. Standard DARTEL segmentation was performed on T1 images to extract gray matter, white matter, and cerebrospinal fluid posterior probability distribution. The resulting segmentations were used to create a dedicated DARTEL template that was used to normalize all T1 images (Ashburner, 2007).

Resting state images were processed using a standard processing pipeline that included signal heterogeneity correction using ANTS NI4TK, slice timing, motion correction, co-registration on the T1 images, normalization (based on the T1 images), and spatial smoothing (FWHM=6 mm).

Resting-state metrics

ALFF, ReHo, and Voxel-Mirrored Homotopic Connectivity (VMHC) were estimated to evaluate local alterations of signal fluctuations. ALFF, ReHo and VMHC maps were prepared with the REST toolbox (Resting-State fMRI Data Analysis Toolkit V1.8, REST-Group, http://www.restfmri.net). Functional images were detrended and filtered (0.01-0.08 Hz). Smoothing was performed after ReHo score calculation to avoid artificially increasing the similarity between neighboring voxels. Maps were z-scored. The average gray matter ALFF, ReHo and VMHC values were extracted from 116 regions using the AAL parcellation atlas (AAL 116 toolbox, Tzourio-Mazoyer et al. 2002). Based on our previous fMRI studies ^34–36 and literature data ³, additional analyses focused on regions implicated in suicidal vulnerability (Figure 1): 1) orbitofrontal cortex (OFC): orbital parts of the inferior frontal gyrus (IFG), middle frontal gyrus and medial frontal gyrus (corresponding to the Brodmann areas (BA) 11/47); 2) ventrolateral prefrontal cortex (VLPFC): pars opercularis of the IFG (BA44/45); 3) dorsal prefrontal cortex (DPFC): middle frontal gyrus (BA 8/9/46); 4) anterior cingulate cortex (ACC) (BA 24/32); and 5) insula.

Statistical analysis

Statistical analyses were performed with R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria). A general linear model was used to model each regional measure as an outcome, while adjusting for age, sex, and education level. To identify the main group effects, a type II analysis of variance was performed with the fitted model. A false discovery rate (FDR) procedure was used for each set of rs-fMRI metrics to correct for multiple comparisons and post hoc analyses were performed for regions with a FDR p <.05. Exploratory correlation analyses were performed to examine possible associations between rs-fMRI metrics with a main group effect and clinical variables (depression, psychological pain intensity and suicidal ideation intensity) in all patients and also suicidal intent and lethality of last suicide attempt in SAs. Exploratory correlation analyses were also performed to identify possible associations between rs-fMRI metrics and peripheral inflammation markers in all patients. All correlation analyses were followed by multiple comparison correction (FDR).

Description of the sample

The sociodemographic and clinical characteristics of the different groups are presented in Table 1. Education level was higher in HCs than SAs and current psychological pain was lower in HC than in AC and SA. Suicidal ideation (severity and intensity according to the C-SSRS) was higher in SAs than ACs. The serum concentration of CRP, but not of IL-6 and TNF-α, was higher in SAs than HCs and ACs.

Table 1

Description of the sample
	Correlation between suicidal ideation intensity (C-SSRS) and rs-fMRI metrics in patients (AC, SA)			Correlation between suicidal intent (SIS) and rs-fMRI metrics in suicide attempters (SA)
Region	ALFF	ReHo	VMHC	ALFF	ReHo	VMHC
Frontal Middle L	0.2	0.03	-0.09	0.02	-0.09	-0.08
Frontal Middle R	0.1	-0.16	-0.21	0.04	0.08	-0.04
Frontal Middle Orbital L	0.17	0.17	0.06	0.21	0.31	0.24
Frontal Middle Orbital R	0.22	0.04	-0.03	-0.03	0.04	0.23
Frontal Inferior Opercular L	-0.32*	-0.16	-0.41**	-0.43	-0.32	-0.29
Frontal Inferior Opercular R	-0.41**	-0.34*	-0.47**	-0.36	-0.09	-0.38
Frontal Inferior Orbital L	0.02	0.05	0.22	0.25	0.41	0.25
Frontal Inferior Orbital R	0.06	0.1	0.21	0.14	0.41	0.11
Frontal Medial Orbital L	0.24	0.26	0.22	0.04	0.29	0.19
Frontal Medial Orbital R	0.29	0.1	0.2	-0.22	0.25	0.14
Insula L	-0.18	0.31	0.11	-0.15	-0.09	-0.27
Insula R	-0.25	0.24	-0.01	-0.19	0.08	-0.24
Cingulum Anterior L	0.13	0.17	0.18	-0.16	0.31	0.12
Cingulum Anterior R	0.03	0.1	0.25	-0.23	0.04	0.16
Significance: *p < 0.01; p < 0.05
AC: Affective Controls; C-SSRS: Columbia Suicide Severity Rating Scale; L: left; R: right; SA: Suicide attempters; SIS: Suicidal Intent Scale

Main group effect on rs-fMRI metrics

An overall main group effect on ALFF values was observed in the left and right pars opercularis of the IFG (F = 6.75. p = 0.033 and F = 5.66. p = 0.040, respectively). After post-hoc correction for multiple testing, the ALFF values in the left and right pars opercularis of the IFG were lower in SAs than in ACs and HCs (Fig. 2). This result remained significant when considering only the two patient groups and after adjustment for suicidal ideation intensity and CRP concentration (not shown).

There was no main group effect on ReHo and VHMC values.

Correlation between rs-fMRI values in the pars opercularis of the IFG and clinical measures

Correlation analyses focused on the rs-fMRI metrics of the left and right pars opercularis of the IFG (Table 2). In all patients (ACs and SAs), depression level was negatively correlated with the VHMC values (r = − 0.34 for the right and r = − 0.33 for the left pars opercularis, p < 0.05), and current psychological pain level was negatively correlated with the ReHo values (r = − 0.34 for the right side and r = − 0.38 for the left side, p < 0.05). Suicidal ideation intensity was negatively correlated with all rs-fMRI metrics of right and left pars opercularis of the IFG, except for the ReHo value of the left side. After FDR correction, only the correlations between suicidal ideation intensity and rs-fMRI metrics in the pars opercularis of the IFG (except for the ALFF of the left side) remained significant.

Table 2 : Correlations between rs-fMRI metrics, suicidal ideation, and suicidal intent

	Correlation between suicidal ideation intensity (C-SSRS) and rs-fMRI metrics in patients (AC, SA)			Correlation between suicidal intent (SIS) and rs-fMRI metrics in suicide attempters (SA)
Region	ALFF	ReHo	VMHC	ALFF	ReHo	VMHC
Frontal Middle L	0.2	0.03	-0.09	0.02	-0.09	-0.08
Frontal Middle R	0.1	-0.16	-0.21	0.04	0.08	-0.04
Frontal Middle Orbital L	0.17	0.17	0.06	0.21	0.31	0.24
Frontal Middle Orbital R	0.22	0.04	-0.03	-0.03	0.04	0.23
Frontal Inferior Opercular L	-0.32*	-0.16	-0.41**	-0.43	-0.32	-0.29
Frontal Inferior Opercular R	-0.41**	-0.34*	-0.47**	-0.36	-0.09	-0.38
Frontal Inferior Orbital L	0.02	0.05	0.22	0.25	0.41	0.25
Frontal Inferior Orbital R	0.06	0.1	0.21	0.14	0.41	0.11
Frontal Medial Orbital L	0.24	0.26	0.22	0.04	0.29	0.19
Frontal Medial Orbital R	0.29	0.1	0.2	-0.22	0.25	0.14
Insula L	-0.18	0.31	0.11	-0.15	-0.09	-0.27
Insula R	-0.25	0.24	-0.01	-0.19	0.08	-0.24
Cingulum Anterior L	0.13	0.17	0.18	-0.16	0.31	0.12
Cingulum Anterior R	0.03	0.1	0.25	-0.23	0.04	0.16

Significance: **p <0.01; *p <0.05

AC: Affective Controls; C-SSRS: Columbia Suicide Severity Rating Scale; L: left; R: right; SA: Suicide attempters; SIS: Suicidal Intent Scale

In SAs, the suicidal intent of the last attempt was not correlated with the rs-fMRI metrics for the bilateral pars opercularis of the IFG (Table 2). Correlation analyses between rs-fMRI metrics and lethality of the last suicide attempt could not be performed due to the variable distribution.

Correlation between peripheral inflammation markers (CRP, IL-6 and TNF-α) and rs-fMRI metrics in patients.

The level of pro-inflammatory cytokines was positively correlated with the ALFF value of left (r = 0.46, p < 0.01 for IL-6 and r = 0.4, p < 0.5 for TNF-α) and right (r = 0.52, p < 0.01 for IL-6 and r = 0.53, p < 0.01 for TNF-α) insula (Table 3). These correlations were not significant after FDR correction.

Table 3: Correlations between rs-fMRI metrics and peripheral blood - inflammation markers in patients with MDD (AC and SA).

	Correlation between IL-6 concentration and rs-fMRI metrics in patients (AC, SA)			Correlation between CRP concentration and rs-fMRI measures in patients (AC, SA)			Correlation between TNF-α concentration and rs-fMRI metrics in patients (AC, SA)
Region	ALFF	ReHo	ALFF	ReHo	VMHC	VMHC	ALFF	ReHo	VMHC
Frontal Middle L	-0.19	-0.03	-0.21	-0.11	0.28	0.03	-0.17	-0.04	0.04
Frontal Middle R	-0.26	-0.15	-0.28	-0.08	0.24	0.02	-0.26	-0.17	0.02
Frontal Middle Orbital L	-0.19	-0.15	-0.09	-0.25	0.17	-0.12	-0.2	-0.16	-0.11
Frontal Middle Orbital R	-0.24	-0.08	-0.09	-0.14	0.24	-0.07	-0.27	-0.06	-0.05
Frontal Inferior Opercular L	0.02	-0.09	-0.07	0	0.25	0.29	0.02	-0.07	0.28
Frontal Inferior Opercular R	0.12	0.04	-0.28	-0.12	0.15	0.27	0.12	0.04	0.27
Frontal Inferior Orbital L	0.01	-0.04	0.03	-0.18	0.01	-0.03	0	-0.04	-0.03
Frontal Inferior Orbital R	-0.13	-0.05	-0.15	-0.24	0.05	-0.04	-0.13	-0.05	-0.03
Frontal Medial Orbital L	-0.21	-0.15	-0.16	-0.04	0.2	-0.17	-0.2	-0.15	-0.15
Frontal Medial Orbital R	-0.13	-0.07	0.01	-0.1	0.05	-0.13	-0.13	-0.06	-0.11
Insula L	0.46**	-0.07	0.2	0.27	0.09	-0.06	0.4*	-0.07	-0.05
Insula R	0.52**	-0.16	0.13	0.19	0.03	-0.03	0.53**	-0.16	-0.02
Cingulum Anterior L	0.28	0.03	-0.11	-0.3	-0.36	0.18	0.27	0.02	0.18
Cingulum Anterior R	0.27	-0.05	0.04	-0.27	-0.25	0.16	0.27	-0.04	0.16

Significance: **p <0.01; *p <0.05 without correction for multiple tests. No significant correlation after correction for multiple tests.

AC: Affective Controls; C-SSRS: Columbia Suicide Severity Rating Scale; L: left; R: right; SA: Suicide attempters; SIS: Suicidal Intent Scale

The main result of this study is the association between altered functional connectivity of the pars opercularis of the IFG (which is part of the VLPFC) and suicide attempt and suicidal ideation in patients with depression. ALFF values were lower in the left pars opercularis of the IFG in SAs compared with ACs and HCs. Despite the negative correlation between ALFF values in this region and suicidal ideation intensity, these results are not explained only by suicidal ideation because the between-group difference (SAs vs. ACs) remained significant after controlling for suicidal ideation. Therefore, our results bring more weight to the hypothesis that the neurobiology underpinnings of suicidal ideation and suicidal act overlap, but are not identical ³⁷.

Our results are in accordance with previous studies showing lower ALFF values in the VLPFC in SAs compared with patients with depression ^19,38. In addition, decreased IFG functional connectivity was described in SAs compared with HCs ³⁹ and in patients at high vs. low suicidal risk ⁷. ALFF has been shown to be directly correlated with the regional glucose metabolism rate ⁴⁰ and with task-based BOLD responses ⁴¹. Interestingly, previous studies showed lower glucose uptake in the ventral prefrontal cortex in SAs ⁴² and altered VLPFC activity in SAs when engaging in cognitive tasks, such as verbal fluency ⁴³, executive functions ⁴⁴, social threats ³⁶ and decision-making ⁴⁵.

The correlation analysis between rs-fMRI metrics and suicidal characteristics was then performed to gain insights into the neural mechanisms of suicidal risk factors that may be more predictive of suicide completion. For instance, severity of suicidal ideation and intent of suicide attempts are strongly associated with the suicidal act lethality ^46,47. Intensity of suicidal ideation and psychological pain (but not depression) were negatively correlated with all rs-fMRI metrics (ALFF, ReHo, and VHMC values) of the pars opercularis of the IFG. Dysfunctions of the pars opercularis have been associated with impaired verbal fluency ⁴⁸ and high levels of psychological pain ⁴⁹, two typical features of suicidal patients ^50,51. Moreover, psychological pain has been associated with poor phonemic verbal fluency performance in men ⁵² and with suicidal ideation ³⁰. Individuals who are less able to verbalize emotions or distress are more likely to use non-verbal communication, such as self-harm ⁵³. The IFG also plays a critical role in cognitive control and response inhibition ⁵⁴. Indeed, impaired response inhibition in patients with left IFG damage is a significant predictor of future suicidal ideation or act ⁵⁵. Our results suggest a functional disruption of the IFG pars opercularis that may exacerbate suicidal ideation and psychological pain due to language impairment, and facilitate suicidal behavior through its involvement in the circuits mediating cognitive control. Alterations in the inferior frontal gyrus connections, possibly with the ventromedial prefrontal cortex, as suggested by ³, could then contribute to the transition from suicidal ideation to act.

However, we did not confirm the association between suicidal ideation and ALFF values of hippocampus, thalamus, caudate ⁵⁶, cingulate cortex, orbitofrontal cortex, inferior temporal gyrus ⁵⁷, and parietal regions ¹⁷. This lack of replication of biological findings is a major issue in psychiatry ⁵⁸.

To our knowledge, this is the first study in which VMHC was measured in suicidal patients. VMHC assesses the functional homotopy (i.e., interhemispheric resting-state functional connectivity) by quantifying the functional connectivity between a voxel and its mirrored counterpart in the contralateral hemisphere. Functional homotopy is considered one of the most salient features of the brain intrinsic functional architecture ⁵⁹. Previous studies reported decreased VMHC in patients with depression (compared with controls) in cuneus, posterior cingulate cortex/precuneus and superior frontal gyrus ⁶⁰, and a negative correlation between illness duration and VMHC of the fusiform gyrus ⁶¹. However, no study investigated its association with suicidality. In the present study, VMHC (in addition to ALFF and ReHo) was correlated with suicidal ideation intensity, but not with history of suicide attempt. Altogether, our results add to the hypothesis of altered brain functional hierarchy in suicidal patients.

Considering peripheral inflammation markers, high level of CRP was associated with history of suicidal acts, as previously reported (Courtet et al., 2015). However, CRP was not associated with rs-fMRI metrics in all patients (SAs and ACs). This may partly be explained by the fact that in the present analysis, CRP was considered a continuous variable and not a categorical variable (cut off > 3 mg/L) as done by Aruldass et al. (2021). The correlation between concentrations of pro-inflammatory cytokines and the rs-fMRI metrics of insula did not remain after FDR correction. Of note, previous studies reported a negative correlation between IL-6 and functional connectivity in networks involving this region ^24,62. Untargeted proteomic approaches – concerning inflammatory markers - may be better suited for identify a possible association of rs-fMRI metrics with suicidal measures in depressed patients.

Our study has several limitations. First the sample size was small. However, our main results are mainly consistent with literature data. Second, the potential association between functional connectivity and number of past suicide attempts could not be assessed due to the variable distribution.

To conclude, this study shows that resting state functional connectivity of the VLPFC is altered in SAs and is negatively influenced by the intensity of suicidal ideation. The growing evidence of the involvement of this region in suicidal behaviors suggests that these metrics could be candidate biomarkers to detect patients at risk and to improve suicide prevention.

FUNDINGS

This study was funded by AOI Montpellier (2015) and the Etablissement Français du Sang - EFS.

ACKNOWLEDGEMENTS: We thank Claire Belloc and Myriam Benramdane for data management. We thank Elisabetta Andermascher for her careful reading. We would like to thank Charles Antoine Arthaud, Marie Ange Eyraud, Amélie Prier from the Etablissement Français du Sang, Auvergne Rhône-Alpes & SAINBIOSE,U1059, France, for technical support throughout our investigations. We thank Dr Hind Hamzeh-Cognasse from Université Jean Monnet Saint-Étienne, Mines Saint-Étienne, INSERM, SAINBIOSE U1059, Saint-Étienne for her participation in biological analyses.

CONFLICTS of INTEREST None

Diagnostic and statistical manual of mental disorders: DSM-5^TM, 5th ed. American Psychiatric Publishing, Inc.: Arlington, VA, US, 2013.
Mann JJ, Rizk MM. A Brain-Centric Model of Suicidal Behavior. Am J Psychiatry 2020; 177: 902–916.
Schmaal L, van Harmelen A-L, Chatzi V, Lippard ETC, Toenders YJ, Averill LA et al. Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies. Mol Psychiatry 2020; 25: 408–427.
Zuo X-N, Xing X-X. Test-retest reliabilities of resting-state FMRI measurements in human brain functional connectomics: a systems neuroscience perspective. Neurosci Biobehav Rev 2014; 45: 100–118.
Serafini G, Pardini M, Pompili M, Girardi P, Amore M. Understanding Suicidal Behavior: The Contribution of Recent Resting-State fMRI Techniques. Front Psychiatry 2016; 7.https://www.frontiersin.org/articles/10.3389/fpsyt.2016.00069 (accessed 7 Feb2023).
Ho TC, Walker JC, Teresi GI, Kulla A, Kirshenbaum JS, Gifuni AJ et al. Default mode and salience network alterations in suicidal and non-suicidal self-injurious thoughts and behaviors in adolescents with depression. Transl Psychiatry 2021; 11: 1–14.
Kim G-W, Farabaugh AH, Vetterman R, Holmes A, Nyer M, Nasiriavanaki Z et al. Diminished frontal pole size and functional connectivity in young adults with high suicidality. J Affect Disord 2022; 310: 484–492.
Cao J, Chen X, Chen J, Ai M, Gan Y, Wang W et al. Resting-state functional MRI of abnormal baseline brain activity in young depressed patients with and without suicidal behavior. J Affect Disord 2016; 205: 252–263.
Chin Fatt CR, Jha MK, Minhajuddin A, Mayes T, Ballard ED, Trivedi MH. Dysfunction of default mode network is associated with active suicidal ideation in youths and young adults with depression: Findings from the T-RAD study. J Psychiatr Res 2021; 142: 258–262.
Zhang S, Chen J, Kuang L, Cao J, Zhang H, Ai M et al. Association between abnormal default mode network activity and suicidality in depressed adolescents. BMC Psychiatry 2016; 16: 337.
Jiang H, Zhu R, Tian S, Wang H, Chen Z, Wang X et al. Structural–functional decoupling predicts suicide attempts in bipolar disorder patients with a current major depressive episode. Neuropsychopharmacology 2020; 45: 1735–1742.
Jung J, Choi S, Han K-M, Kim A, Kang W, Paik J-W et al. Alterations in functional brain networks in depressed patients with a suicide attempt history. Neuropsychopharmacology 2020; 45: 964–974.
Kang S-G, Na K-S, Choi J-W, Kim J-H, Son Y-D, Lee YJ. Resting-state functional connectivity of the amygdala in suicide attempters with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2017; 77: 222–227.
Stumps A, Jagger-Rickels A, Rothlein D, Amick M, Park H, Evans T et al. Connectome-based functional connectivity markers of suicide attempt. J Affect Disord 2021; 283: 430–440.
Yang J, Liu Z, Tao H, Cheng Y, Fan Z, Sun F et al. Aberrant brain dynamics in major depressive disorder with suicidal ideation. J Affect Disord 2022; 314: 263–270.
Fan T, Wu X, Yao L, Dong J. Abnormal baseline brain activity in suicidal and non-suicidal patients with major depressive disorder. Neurosci Lett 2013; 534: 35–40.
Yang Y, Li X, Cui Y, Liu K, Qu H, Lu Y et al. Reduced Gray Matter Volume in Orbitofrontal Cortex Across Schizophrenia, Major Depressive Disorder, and Bipolar Disorder: A Comparative Imaging Study. Front Neurosci 2022; 16: 919272.
Stange JP, Jenkins LM, Pocius S, Kreutzer K, Bessette KL, DelDonno SR et al. Using resting-state intrinsic network connectivity to identify suicide risk in mood disorders. Psychol Med 2020; 50: 2324–2334.
Wagner G, Li M, Sacchet MD, Richard-Devantoy S, Turecki G, Bär K-J et al. Functional network alterations differently associated with suicidal ideas and acts in depressed patients: an indirect support to the transition model. Transl Psychiatry 2021; 11: 1–11.
Courtet P, Giner L, Seneque M, Guillaume S, Olie E, Ducasse D. Neuroinflammation in suicide: Toward a comprehensive model. World J Biol Psychiatry Off J World Fed Soc Biol Psychiatry 2016; 17: 564–586.
Courtet Ph, Jaussent I, Genty C, Dupuy AM, Guillaume S, Ducasse D et al. Increased CRP levels may be a trait marker of suicidal attempt. Eur Neuropsychopharmacol 2015; 25: 1824–1831.
Black C, Miller BJ. Meta-Analysis of Cytokines and Chemokines in Suicidality: Distinguishing Suicidal Versus Nonsuicidal Patients. Biol Psychiatry 2015; 78: 28–37.
Ducasse D, Olié E, Guillaume S, Artéro S, Courtet P. A meta-analysis of cytokines in suicidal behavior. Brain Behav Immun 2015; 46: 203–211.
Aruldass AR, Kitzbichler MG, Morgan SE, Lim S, Lynall M-E, Turner L et al. Dysconnectivity of a brain functional network was associated with blood inflammatory markers in depression. Brain Behav Immun 2021; 98: 299–309.
Felger JC, Li Z, Haroon E, Woolwine BJ, Jung MY, Hu X et al. Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry 2016; 21: 1358–1365.
Yin L, Xu X, Chen G, Mehta ND, Haroon E, Miller AH et al. Inflammation and decreased functional connectivity in a widely-distributed network in depression: Centralized effects in the ventral medial prefrontal cortex. Brain Behav Immun 2019; 80: 657–666.
Marsland AL, Walsh C, Lockwood K, John-Henderson NA. The effects of acute psychological stress on circulating and stimulated inflammatory markers: A systematic review and meta-analysis. Brain Behav Immun 2017; 64: 208–219.
Tu P-C, Li C-T, Lin W-C, Chen M-H, Su T-P, Bai Y-M. Structural and functional correlates of serum soluble IL-6 receptor level in patients with bipolar disorder. J Affect Disord 2017; 219: 172–177.
Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH. The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med 1996; 26: 477–486.
Olié E, Guillaume S, Jaussent I, Courtet P, Jollant F. Higher psychological pain during a major depressive episode may be a factor of vulnerability to suicidal ideation and act. J Affect Disord 2010; 120: 226–230.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 2011; 168: 1266–1277.
Beck AT, Kovacs M, Weissman A. Assessment of suicidal intention: The Scale for Suicide Ideation. J Consult Clin Psychol 1979; 47: 343–352.
Sackeim HA. The definition and meaning of treatment-resistant depression. J Clin Psychiatry 2001; 62 Suppl 16: 10–17.
Olié E, Husky M, Bars EL, Deverdun J, de Champfleur NM, Crespo AA et al. Prefrontal activity during experimental ostracism and daily psychache in suicide attempters. J Affect Disord 2021; 285: 63–68.
Olié E, Jollant F, Deverdun J, de Champfleur NM, Cyprien F, Le Bars E et al. The experience of social exclusion in women with a history of suicidal acts: a neuroimaging study. Sci Rep 2017; 7: 89.
Olié E, Ding Y, Le Bars E, de Champfleur NM, Mura T, Bonafé A et al. Processing of decision-making and social threat in patients with history of suicidal attempt: A neuroimaging replication study. Psychiatry Res Neuroimaging 2015; 234: 369–377.
Klonsky ED, May AM. The Three-Step Theory (3ST): A new theory of suicide rooted in the “ideation-to-action” framework. Int J Cogn Ther 2015; 8: 114–129.
Cao J, Chen J, Kuang L, Ai M, Fang W, Gan Y et al. Abnormal regional homogeneity in young adult suicide attempters with no diagnosable psychiatric disorder: A resting state functional magnetic imaging study. Psychiatry Res Neuroimaging 2015; 231: 95–102.
Wagner G, de la Cruz F, Köhler S, Pereira F, Richard-Devantoy S, Turecki G et al. Connectomics-Based Functional Network Alterations in both Depressed Patients with Suicidal Behavior and Healthy Relatives of Suicide Victims. Sci Rep 2019; 9: 14330.
Nugent AC, Martinez A, D’Alfonso A, Zarate CA, Theodore WH. The relationship between glucose metabolism, resting-state fMRI BOLD signal, and GABAA-binding potential: a preliminary study in healthy subjects and those with temporal lobe epilepsy. J Cereb Blood Flow Metab 2015; 35: 583–591.
Tomasi D, Volkow ND. Association Between Brain Activation and Functional Connectivity. Cereb Cortex 2019; 29: 1984–1996.
Oquendo MA, Placidi GPA, Malone KM, Campbell C, Keilp J, Brodsky B et al. Positron Emission Tomography of Regional Brain Metabolic Responses to a Serotonergic Challenge and Lethality of Suicide Attempts in Major Depression. Arch Gen Psychiatry 2003; 60: 14–22.
Audenaert K, Goethals I, Van Laere K, Lahorte P, Brans B, Versijpt J et al. SPECT neuropsychological activation procedure with the Verbal Fluency Test in attempted suicide patients. Nucl Med Commun 2002; 23: 907–916.
Dai Z, Zhou H, Zhang W, Tang H, Wang T, Chen Z et al. Alpha-beta decoupling relevant to inhibition deficits leads to suicide attempt in major depressive disorder. J Affect Disord 2022; 314: 168–175.
Jollant F, Lawrence NS, Olie E, O’Daly O, Malafosse A, Courtet P et al. Decreased activation of lateral orbitofrontal cortex during risky choices under uncertainty is associated with disadvantageous decision-making and suicidal behavior. NeuroImage 2010; 51: 1275–1281.
Hasley JP, Ghosh B, Huggins J, Bell MR, Adler LE, Shroyer ALW. A review of ‘suicidal intent’ within the existing suicide literature. Suicide Life Threat Behav 2008; 38: 576–591.
Shelef L, Klomek AB, Fruchter E, Kedem R, Mann JJ, Zalsman G. Suicide ideation severity is associated with severe suicide attempts in a military setting. Eur Psychiatry 2019; 61: 49–55.
Bookheimer S. Functional MRI of language: new approaches to understanding the cortical organization of semantic processing. Annu Rev Neurosci 2002; 25: 151–188.
van Heeringen K, Van den Abbeele D, Vervaet M, Soenen L, Audenaert K. The functional neuroanatomy of mental pain in depression. Psychiatry Res 2010; 181: 141–144.
Baryshnikov I, Isometsä E. Psychological pain and suicidal behavior: A review. Front Psychiatry 2022; 13.https://www.frontiersin.org/articles/10.3389/fpsyt.2022.981353 (accessed 7 Feb2023).
Keilp JG, Sackeim HA, Brodsky BS, Oquendo MA, Malone KM, Mann JJ. Neuropsychological dysfunction in depressed suicide attempters. Am J Psychiatry 2001; 158: 735–741.
Richard-Devantoy S, Bertrand J-A, Béziat S, Jaussent I, Cazals A, Ducasse D et al. Psychological pain and depression: it’s hard to speak when it hurts. Int J Psychiatry Clin Pract 2021; 25: 180–186.
Gunnell D, Bennewith O, Peters TJ, House A, Hawton K. The epidemiology and management of self-harm amongst adults in England. J Public Health Oxf Engl 2005; 27: 67–73.
Zhang R, Geng X, Lee TMC. Large-scale functional neural network correlates of response inhibition: an fMRI meta-analysis. Brain Struct Funct 2017; 222: 3973–3990.
Tarter RE, Kirisci L, Reynolds M, Mezzich A. Neurobehavior disinhibition in childhood predicts suicide potential and substance use disorder by young adulthood. Drug Alcohol Depend 2004; 76: S45–S52.
Lan MJ, Rizk MM, Pantazatos SP, Rubin-Falcone H, Miller JM, Sublette ME et al. Resting-state amplitude of low-frequency fluctuation is associated with suicidal ideation. Depress Anxiety 2019; 36: 433–441.
Li J, Duan X, Cui Q, Chen H, Liao W. More than just statics: temporal dynamics of intrinsic brain activity predicts the suicidal ideation in depressed patients. Psychol Med 2019; 49: 852–860.
Kapur S, Phillips AG, Insel TR. Why has it taken so long for biological psychiatry to develop clinical tests and what to do about it? Mol Psychiatry 2012; 17: 1174–1179.
Salvador R, Suckling J, Coleman MR, Pickard JD, Menon D, Bullmore E. Neurophysiological architecture of functional magnetic resonance images of human brain. Cereb Cortex N Y N 1991 2005; 15: 1332–1342.
Guo W, Liu F, Dai Y, Jiang M, Zhang J, Yu L et al. Decreased interhemispheric resting-state functional connectivity in first-episode, drug-naive major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2013; 41: 24–29.
Wang L, Li K, Zhang Q-E, Zeng Y-W, Jin Z, Dai W-J et al. Interhemispheric Functional Connectivity and Its Relationships with Clinical Characteristics in Major Depressive Disorder: A Resting State fMRI Study. PLOS ONE 2013; 8: e60191.
Chen P, Chen F, Chen G, Zhong S, Gong J, Zhong H et al. Inflammation is associated with decreased functional connectivity of insula in unmedicated bipolar disorder. Brain Behav Immun 2020; 89: 615–622.

The authors have declared there is NO conflict of interest to disclose

Association of Suicidal Status, Inflammation Markers and Resting State Functional Connectivity in Patients with Major Depressive Disorder

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Results

Description of the sample

Main group effect on rs-fMRI metrics

Correlation between rs-fMRI values in the pars opercularis of the IFG and clinical measures

Discussion

Declarations

References

Additional Declarations

Status:

Version 1