Structure-function coupling and hierarchy-specific antidepressant response in major depressive disorder.

BACKGROUND: Extensive research has explored altered structural and functional networks in major depressive disorder (MDD). However, studies examining the relationships between structure and function yielded heterogeneous and inconclusive results. Recent work has suggested that the structure-function relationship is not uniform throughout the brain but varies across different levels of functional hierarchy. This study aims to investigate changes in structure-function couplings (SFC) and their relevance to antidepressant response in MDD from a functional hierarchical perspective. METHODS: We compared regional SFC between individuals with MDD (n = 258) and healthy controls (HC, n = 99) using resting-state functional magnetic resonance imaging and diffusion tensor imaging. We also compared antidepressant non-responders (n = 55) and responders (n = 68, defined by a reduction in depressive severity of >50%). To evaluate variations in altered and response-associated SFC across the functional hierarchy, we ranked significantly different regions by their principal gradient values and assessed patterns of increase or decrease along the gradient axis. The principal gradient value, calculated from 219 healthy individuals in the Human Connectome Project, represents a region's position along the principal gradient axis. RESULTS: Compared to HC, MDD patients exhibited increased SFC in unimodal regions (lower principal gradient) and decreased SFC in transmodal regions (higher principal gradient) (p < 0.001). Responders primarily had higher SFC in unimodal regions and lower SFC in attentional networks (median principal gradient) (p < 0.001). CONCLUSIONS: Our findings reveal opposing SFC alterations in low-level unimodal and high-level transmodal networks, underscoring spatial variability in MDD pathology. Moreover, hierarchy-specific antidepressant effects provide valuable insights into predicting treatment outcomes.

Distinct MRI-based functional and structural connectivity for antidepressant response prediction in major depressive disorder.

OBJECTIVE: Emerging studies have identified treatment-related connectome predictors in major depressive disorder (MDD). However, quantifying treatment-responsive patterns in structural connectivity (SC) and functional connectivity (FC) simultaneously remains underexplored. We aimed to evaluate whether spatial distributions of FC and SC associated treatment responses are shared or unique. METHODS: Diffusion tensor imaging and resting-state functional magnetic resonance imaging were collected from 210 patients with MDD at baseline. We separately developed connectome-based prediction models (CPM) to predict reduction of depressive severity after 6-week monotherapy based on structural, functional, and combined connectomes, then validated them on the external dataset. We identified the predictive SC and FC from CPM with high occurrence frequencies during the cross-validation. RESULTS: Structural connectomes (r = 0.2857, p < 0.0001), functional connectomes (r = 0.2057, p = 0.0025), and their combined CPM (r = 0.4, p < 0.0001) can significantly predict a reduction of depressive severity. We didn't find shared connectivity between predictive FC and SC. Specifically, the most predictive FC stemmed from the default mode network, while predictive SC was mainly characterized by within-network SC of fronto-limbic networks. CONCLUSIONS: These distinct patterns suggest that SC and FC capture unique connectivity concerning the antidepressant response. SIGNIFICANCE: Our findings provide comprehensive insights into the neurophysiology of antidepressants response.

Capturing the Individual Deviations From Normative Models of Brain Structure for Depression Diagnosis and Treatment.

BACKGROUND: The high heterogeneity of depression prevents us from obtaining reproducible and definite anatomical maps of brain structural changes associated with the disorder, which limits the individualized diagnosis and treatment of patients. In this study, we investigated the clinical issues related to depression according to individual deviations from normative ranges of gray matter volume. METHODS: We enrolled 1092 participants, including 187 patients with depression and 905 healthy control participants. Structural magnetic resonance imaging data of healthy control participants from the Human Connectome Project (n = 510) and REST-meta-MDD Project (n = 229) were used to establish a normative model across the life span in adults 18 to 65 years old for each brain region. Deviations from the normative range for 187 patients and 166 healthy control participants recruited from two local hospitals were captured as normative probability maps, which were used to identify the disease risk and treatment-related latent factors. RESULTS: In contrast to case-control results, our normative modeling approach revealed highly individualized patterns of anatomic abnormalities in depressed patients (less than 11% extreme deviation overlapping for any regions). Based on our classification framework, models trained with individual normative probability maps (area under the receiver operating characteristic curve range, 0.7146-0.7836) showed better performance than models trained with original gray matter volume values (area under the receiver operating characteristic curve range, 0.6800-0.7036), which was verified in an independent external test set. Furthermore, different latent brain structural factors in relation to antidepressant treatment were revealed by a Bayesian model based on normative probability maps, suggesting distinct treatment response and inclination. CONCLUSIONS: Capturing personalized deviations from a normative range could help in understanding the heterogeneous neurobiology of depression and thus guide clinical diagnosis and treatment of depression.

The altered temporal properties of dynamic functional connectivity associated with suicide attempt in bipolar disorders.

OBJECTIVE: The suicide risk in bipolar disorder (BD) is the highest among psychiatric disorders, and the neurobiological mechanism of suicide in BD remains unclear. The study aimed to investigate the underlying relevance between the implicated abnormalities of dynamic functional connectivity (FC) and suicide attempt (SA) in BD. METHODS: We used the sliding window method to analyze the dynamic FC patterns from resting-state functional MRI data in 81 healthy controls (HC) and 114 BD patients (50 with SA and 64 with none SA). Then, the temporal properties of dynamic FC and the relationship between altered measures and clinical variables were explored. RESULTS: We found that one of the five captured brain functional states was more associated with SA. The SA patients showed significantly increased fractional window and dwell time in the suicide-related state, along with increased number of state transitions compared with none SA (NSA). In addition, the connections within subcortical network-subcortical network (SubC-SubC), default mode network-subcortical network (DMN-SubC), and attention network-subcortical network (AN-SubC) were significantly changed in SA patients relative to NSA and HC in the suicide-related state. Crucially, the above-altered measures were significantly correlated with suicide risk. CONCLUSIONS: Our findings suggested that the impaired dynamic FC within SubC-SubC, DMN-SubC, and AN-SubC were the important underlying mechanism in understanding SA for BD patients. It highlights the temporal properties of whole-brain dynamic FC could serve as the valuable biomarker for suicide risk assessment in BD.

Classification of bipolar disorders using the multilayer modularity in dynamic minimum spanning tree from resting state fMRI.

The diagnosis of bipolar disorders (BD) mainly depends on the clinical history and behavior observation, while only using clinical tools often limits the diagnosis accuracy. The study aimed to create a novel BD diagnosis framework using multilayer modularity in the dynamic minimum spanning tree (MST). We collected 45 un-medicated BD patients and 47 healthy controls (HC). The sliding window approach was utilized to construct dynamic MST via resting-state functional magnetic resonance imaging (fMRI) data. Firstly, we used three null models to explore the effectiveness of multilayer modularity in dynamic MST. Furthermore, the module allegiance exacted from dynamic MST was applied to train a classifier to discriminate BD patients. Finally, we explored the influence of the FC estimator and MST scale on the performance of the model. The findings indicated that multilayer modularity in the dynamic MST was not a random process in the human brain. And the model achieved an accuracy of 83.70% for identifying BD patients. In addition, we found the default mode network, subcortical network (SubC), and attention network played a key role in the classification. These findings suggested that the multilayer modularity in dynamic MST could highlight the difference between HC and BD patients, which opened up a new diagnostic tool for BD patients. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-022-09907-x.

Prediction of suicidality in bipolar disorder using variability of intrinsic brain activity and machine learning.

Bipolar disorder (BD) is associated with marked suicidal susceptibility, particularly during a major depressive episode. However, the evaluation of suicidal risk remains challenging since it relies mainly on self-reported information from patients. Hence, it is necessary to complement neuroimaging features with advanced machine learning techniques in order to predict suicidal behavior in BD patients. In this study, a total of 288 participants, including 75 BD suicide attempters, 101 BD nonattempters and 112 healthy controls, underwent a resting-state functional magnetic resonance imaging (rs-fMRI). Intrinsic brain activity was measured by amplitude of low-frequency fluctuation (ALFF). We trained and tested a two-level k-nearest neighbors (k-NN) model based on resting-state variability of ALFF with fivefold cross-validation. BD suicide attempters had increased dynamic ALFF values in the right anterior cingulate cortex, left thalamus and right precuneus. Compared to other machine learning methods, our proposed framework had a promising performance with 83.52% accuracy, 78.75% sensitivity and 87.50% specificity. The trained models could also replicate and validate the results in an independent cohort with 72.72% accuracy. These findings based on a relatively large data set, provide a promising way of combining fMRI data with machine learning technique to reliably predict suicide attempt at an individual level in bipolar depression. Overall, this work might enhance our understanding of the neurobiology of suicidal behavior by detecting clinically defined disruptions in the dynamics of instinct brain activity.

Gamma band VMPFC-PreCG.L connection variation after the onset of negative emotional stimuli can predict mania in depressive patients.

OBJECTIVE: Because of the similar clinical symptoms, it is difficult to distinguish unipolar disorder (UD) from bipolar disorder (BD) in the depressive episode using the available clinical features, especially for those who meet the diagnostic criteria of UD, however, experience the manic episode during the follow-up (tBD). METHODS: Magnetoencephalography recordings during a sad expression recognition task were obtained from 81 patients (27 BD, 24 tBD, 30 UD) and 26 healthy controls (HCs). Source analysis was applied to localize 64 regions of interest in the low gamma band (30-50 Hz). Regional functional connections (FCs) were constructed respectively within three time periods (early: 0-200 ms, middle: 200-400 ms, and post: 400-600 ms). The network-based statistic method was used to explore the abnormal connection patterns in tBD compared to UD and HC. BD was applied to explore whether such abnormality is still significant between every two groups of BD, tBD, UD, and HC. RESULTS: The VMPFC-PreCG.L connection was found to be a significantly different connection between tBD and UD in the early time period and between tBD and BD in the middle time period. Furthermore, the middle/early time period ratio of FC value of VMPFC-PreCG.L connection was negatively correlated with the bipolarity index in tBD. CONCLUSIONS: The VMPFC-PreCG.L connection in different time periods after the onset of sad facial stimuli may be a potential biomarker to distinguish the different states of BD. The FC ratio of VMPFC-PreCG.L connection may predict whether patients with depressive episodes subsequently develop mania.

Shared and unique imaging-derived endo-phenotypes of two typical antidepressant-applicative depressive patients.

OBJECTIVES: Determining the clinical homogeneous and heterogeneous sets among depressive patients is the key to facilitate individual-level treatment decision. METHODS: The diffusion tensor imaging (DTI) data of 62 patients with major depressive disorder (MDD) and 39 healthy controls were used to construct a Latent Dirichlet Allocation (LDA) Bayesian model. Another 48 MDD patients were used to verify the robustness. The LDA model was employed to identify both shared and unique imaging-derived factors of two typically antidepressant-targeted depressive patients, selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Furthermore, we applied canonical correlation analysis (CCA) between each factor loading and Hamilton depression rating scale (HAMD) sub-score, to explore the potential neurophysiological significance of each factor. RESULTS: The results revealed the imaging-derived connectional fingerprint of all patients could be situated along three latent factor dimensions; such results were also verified by the out-of-sample dataset. Factor 1, uniquely expressed by SNRI-targeted patients, was associated with retardation (r = 0.4, p = 0.037) and characterized by coupling patterns between default mode network and cognitive control network. Factor 3, uniquely expressed by SSRI-targeted patients, was associated with cognitive impairment (r = 0.36, p = 0.047) and characterized by coupling patterns within cognitive control and attention network, and the connectivity between threat and reward network. Shared factor 2, characterized by coupling patterns within default mode network, was associated with anxiety (r = 0.54, p = 0.005) and sleep disturbance (r = 0.37, p = 0.032). CONCLUSIONS: Our findings suggested that quantification of both homogeneity and heterogeneity within MDD may have the potential to inform rational design of pharmacological therapies. KEY POINTS: • The shared and unique manifestations guiding pharmacotherapy of depressive patients are caused by the homogeneity and heterogeneity of underlying structural connections of the brain. • Both shared and unique factor loadings were found in different antidepressant-targeted patients. • Significant correlations between factor loading and HAMD sub-scores were found.

Partly recovery and compensation in anterior cingulate cortex after SSRI treatment-evidence from multi-voxel pattern analysis over resting state fMRI in depression.

BACKGROUND: Anterior cingulate cortex (ACC) plays an essential role in the pathophysiology of major depressive disorder (MDD) and its treatment. However, it's still unclear whether the effects of disease and antidepressant treatment on ACC perform diversely in neural mechanisms. METHODS: Fifty-nine MDD patients completed resting-state fMRI scanning twice at baseline and after 12-week selective serotonin reuptake inhibitor (SSRI) treatment, respectively in acute state and remission state. Fifty-nine demographically matched healthy controls were enrolled. Using fractional amplitude of low-frequency fluctuation (fALFF) in ACC as features, we performed multi-voxel pattern analysis over pretreatment MDD patients vs health control (HC), and over pretreatment MDD patients vs posttreatment MDD patients. RESULTS: Discriminative regions in ACC for MDD impairment and changes after antidepressants were obtained. The intersection set and difference set were calculated to form ACC subregions of recovered, unrecovered and compensative, respectively. The recovered ACC subregion mainly distributed in rostral ACC (80 %) and the other two subregions had nearly equal distribution over dorsal ACC and rostral ACC. Furthermore, only the compensative subregion had significant changed functional connectivity with cingulo-opercular control network (CON) after antidepressant treatment. LIMITATIONS: The number of subjects was relatively small. The results need to be validated with larger sample sizes and multisite data. CONCLUSIONS: This finding suggested that the local function of ACC was partly recovered on regulating emotion after antidepressant by detecting the common subregional targets of depression impairment and antidepressive effect. Besides, changed fALFF in the compensative ACC subregion and its connectivity with CON may partly compensate for the cognition deficits.

Dynamic connectivity alterations in anterior cingulate cortex associated with suicide attempts in bipolar disorders with a current major depressive episode.

OBJECTIVE: Considering that the physiological mechanism of the anterior cingulate cortex (ACC) in suicide brain remains elusive for bipolar disorder (BD) patients. The study aims to investigate the intrinsic relevance between ACC and suicide attempts (SA) through transient functional connectivity (FC). METHODS: We enrolled 50 un-medicated BD patients with at least one SA, 67 none-suicide attempt patients (NSA) and 75 healthy controls (HCs). The sliding window approach was utilized to study the dynamic FC of ACC via resting-state functional MRI data. Subsequently, we probed into the temporal properties of dynamic FC and then estimated the relationship between dynamic characteristics and clinical variables using the Pearson correlation. RESULTS: We found six distinct FC states in all populations, with one of them being more associated with SA. Compared with NSA and HCs, the suicide-related functional state showed significantly reduced dwell time in SA patients, accompanied by a significantly increased FC strength between the right ACC and the regions within the subcortical (SubC) network. In addition, the number of transitions was significantly increased in SA patients relative to other groups. All these altered indicators were significantly correlated with the suicide risk. CONCLUSIONS: The results suggested that the dysfunction of ACC was relevant to SA from a dynamic FC perspective in BD patients. It highlights the temporal properties in dynamic FC of ACC that could be used as a putative target of suicide risk assessment for BD patients.

Shared and disease-sensitive dysfunction across bipolar and unipolar disorder during depressive episodes: a transdiagnostic study.

Patients with depressive episodes (PDE), such as unipolar disorder (UD) and bipolar disorder (BD), are often defined as distinct diagnostic categories, but increasing converging evidence indicated shared etiologies and pathophysiological characteristics across different clinical diagnoses. We explored whether these transdiagnostic deficits are caused by the common neural substrates across diseases or disease-sensitive mechanisms, or a combination of both. In this study, we utilized a Bayesian model to decompose the resting-state brain activity into multiple hyper- and hypo-activity patterns (refer to as "factors"), so as to explore the shared and disease-sensitive alteration patterns in PDE. The model was constructed over a total of 259 patients (131 UD and 128 BD) with 100 healthy controls as the reference. The other 32 initial depressive episode BD (IDE-BD) patients who had symptoms of mania or hypomania during follow-up were taken as an independent set to estimate the factor composition using the established model for further analysis. We revealed three transdiagnostic alteration factors in PDE. Based on the distribution of factors and the tendency of factor composition at the group level, these factors were defined as BD sensitive factor, UD sensitive factor and shared basic alteration factor. We further found that the factor composition and the ROIs-based alteration degree (mainly involving in orbitofrontal gyrus and part of parietal lobe) were associated with the bipolar index in IDE-BD patients. Our findings contributed to understanding the core transdiagnostic shared and disease-sensitive alterations in PDE and to predicting the risk of emotional state transition in IDE-BD patients.

Disrupted fronto-parietal network and default-mode network gamma interactions distinguishing suicidal ideation and suicide attempt in depression.

BACKGROUND: Precise suicide risk evaluation struggled in Major depressive disorder (MDD), especially for patients with only suicidal-ideation (SI) but without suicide attempt (SA). MDD patients have deficits in negative emotion processing, which is associated with the generation of SI and SA. Given the critical role of gamma oscillations in negative emotion processing, we hypothesize that the transition from SI to SA in MDD could be characterized by abnormal gamma interactions. METHODS: We recruited 162 participants containing 106 MDD patients and 56 healthy controls (HCs). Participants performed facial recognition tasks while magnetoencephalography data were recorded. Time-frequency-representation (TFR) analysis was conducted to identify the dominant spectra differences between MDD and HCs, and then source analysis was applied to localize the region of interests. Furthermore, frequency-specific functional connectivity network were constructed and a semi-supervised clustering algorithm was utilized to predict potential suicide risk. RESULTS: Gamma (50-70 Hz) power was found significantly increased in MDD, mainly residing in regions from fronto-parietal-control-network (FPN), visual-network (VN), default-mode-network (DMN) and salience-network (SN). Based on impaired gamma functional connectivity network between well-established SA group and non-SI group, semi-supervised algorithm clustered patients with only SI into two groups with different suicide risks. Moreover, Inter-network gamma connectivity between FPN and DMN significantly negatively correlated with suicide risk and not confounded by depression severity. CONCLUSION: Inter-network gamma connectivity with FPN and DMN might be the key neuropathological interactions underling the progression from SI to SA. By applying semi-supervised clustering to electrophysiological data, it is possible to predict individual suicide risk.

Functional impairment-based segmentation of anterior cingulate cortex in depression and its relationship with treatment effects.

In major depressive disorder (MDD), the anterior cingulate cortex (ACC) is widely related to depression impairment and antidepressant treatment response. The multiplicity of ACC subdivisions calls for a fine-grained investigation of their functional impairment and recovery profiles. We recorded resting state fMRI signals from 59 MDD patients twice before and after 12-week antidepressant treatment, as well as 59 healthy controls (HCs). With functional connectivity (FC) between each ACC voxel and four regions of interests (bilateral dorsolateral prefrontal cortex [DLPFC] and amygdalae), subdivisions with variable impairment were identified based on groups' dissimilarity values between MDD patients before treatment and HC. The ACC was subdivided into three impairment subdivisions named as MedialACC, DistalACC, and LateralACC according to their dominant locations. Furthermore, the impairment pattern and the recovery pattern were measured based on group statistical analyses. DistalACC impaired more on its FC with left DLPFC, whereas LateralACC showed more serious impairment on its FC with bilateral amygdalae. After treatment, FCs between DistalACC and left DLPFC, and between LateralACC and right amygdala were normalized while impaired FC between LateralACC and left amygdala kept dysfunctional. Subsequently, FC between DistalACC and left DLPFC might contribute to clinical outcome prediction. Our approach could provide an insight into how the ACC was impaired in depression and partly restored after antidepressant treatment, from the perspective of the interaction between ACC subregions and critical frontal and subcortical regions.

Temporal dynamics alterations of spontaneous neuronal activity in anterior cingulate cortex predict suicidal risk in bipolar II patients.

Bipolar disorder type II (BD-II) is linked to an increased suicidal risk. Since a prior suicide attempt (SA) is the single most important risk factor for sequent suicide, the elucidation of involved neural substrates is critical for its prevention. Therefore, we examined the spontaneous brain activity and its temporal variabilities in suicide attempters with bipolar II during a major depressive episode. In this cross-sectional study, 101 patients with BD-II, including 44 suicidal attempters and 57 non-attempters, and 60 non-psychiatric controls underwent a resting-state functional magnetic resonance imaging (fMRI). Participants were assessed with Hamilton Rating Scale for Depression (HAMD) and Nurses, Global Assessment of Suicide Risk (NGASR). The dynamics of low-frequency fluctuation (dALFF) was measured using sliding-window analysis and its correlation with suicidal risk was conducted using Pearson correlation. Compared to non-attempters, suicidal attempters showed an increase in brain activity and temporal dynamics in the anterior cingulate cortex (ACC). In addition, the temporal variabilities of ACC activity positively correlated with suicidal risk (R = 0.45, p = 0.004), while static ACC activity failed to (R = 0.08, p > 0.05). Our findings showed that an aberrant static ALFF and temporal variability could affect suicidal behavior in BD-II patients. However, temporal variability of neuronal activity was more sensitive than static amplitude in reflecting diathesis for suicide in BD-II. Dynamics of brain activity could be considered in developing neuromarkers for suicide prevention.

Serotonin 2A receptor polymorphism rs3803189 mediated by dynamics of default mode network: a potential biomarker for antidepressant early response.

BACKGROUND: Serotonin 2A receptors (HTR2A) play a crucial role in the therapeutic response to antidepressant. The activity of serotonergic system could modulate the connectivity of the default mode network (DMN) in human brain. Our research investigated the influence of the single nucleotide polymorphism (SNP) of HTR2A on the early treatment response of antidepressant and their relation to dynamic changes of DMN for the first time. METHODS: A total of 134 major depressive disorder patients and 95 healthy controls from two independent datasets were enrolled. All subjects have genotyped candidate HTR2A polymorphisms, dynamic brain parameters flexibility and integration were calculated according to the resting-state functional magnetic resonance imaging (rs-fMRI) at baseline. Patients received selective serotonin reuptake inhibitors (SSRIs) treatment with conventional dose in the next two weeks. RESULTS: We found the correlation of the risk-associated variant belonged to HTR2A polymorphism rs3803189 with the achievements of antidepressant early response, and also with the stronger dynamic changes of DMN. Further mediation analysis indicated that the bond between rs3803189 and antidepressant early response was mediated by the integration between the right angular gyrus (AG.R) and the subcortical network (SCN), which were validated over both the main and replication datasets. LIMITATIONS: Except the AG.R-SCN circuit, other factors which influence the relationship between rs3803189 and antidepressant therapy deserve to be explored further. Besides, heterogeneity of samples limited the power of the current result. CONCLUSIONS: Our findings provided a potential biomarker for individual treatment sensitivity and produced positive effects on revealing the complicated gene-brain-disorder relationship.

Aberrant functional connectivity between the suprachiasmatic nucleus and the superior temporal gyrus: Bridging RORA gene polymorphism with diurnal mood variation in major depressive disorder.

Diurnal mood variation (DMV), a common symptom of major depressive disorder (MDD), is associated with circadian related genes and dysregulation of the suprachiasmatic nucleus (SCN). Previous research confirmed that the RORA gene is involved in the regulation of circadian rhythms. In this study, we hypothesized that polymorphisms of RORA may affect DMV symptoms of MDD through functional changes in the SCN. A total of 208 patients diagnosed with depression and 120 control subjects were enrolled and underwent a resting-state functional magnetic resonance imaging (rs-fMRI). Blood samples were collected and genotyping of 9 RORA gene SNPs were performed using next-generation sequencing technology. Patients were categorized as an AA genotype or C allele carriers based on RORA rs72752802 polymorphism. SCN-seed functional connectivity (FC) was compared between the two groups and correlation with severity of DMV was analyzed. Finally, a mediation analysis was performed to further determine FC intermediary effects. We observed that rs72752802 was significantly associated with patients' DMV symptoms. C allele carriers of rs72752802 showed significantly decreased FC between the right SCN and right superior temporal gyrus (rSTG). This was also correlated with DMV symptoms. In addition, the rs72752802 SNP influenced DMV symptoms through intermediary effects of SCN-rSTG connectivity. The study presented here provides a neurological and genetic basis for understanding depressed patients experiencing DMV.

Discriminating Suicide Attempters and Predicting Suicide Risk Using Altered Frontolimbic Resting-State Functional Connectivity in Patients With Bipolar II Disorder.

Bipolar II disorder (BD-II) major depression episode is highly associated with suicidality, and objective neural biomarkers could be key elements to assist in early prevention and intervention. This study aimed to integrate altered brain functionality in the frontolimbic system and machine learning techniques to classify suicidal BD-II patients and predict suicidality risk at the individual level. A cohort of 169 participants were enrolled, including 43 BD-II depression patients with at least one suicide attempt during a current depressive episode (SA), 62 BD-II depression patients without a history of attempted suicide (NSA), and 64 demographically matched healthy controls (HCs). We compared resting-state functional connectivity (rsFC) in the frontolimbic system among the three groups and explored the correlation between abnormal rsFCs and the level of suicide risk (assessed using the Nurses' Global Assessment of Suicide Risk, NGASR) in SA patients. Then, we applied support vector machines (SVMs) to classify SA vs. NSA in BD-II patients and predicted the risk of suicidality. SA patients showed significantly decreased frontolimbic rsFCs compared to NSA patients. The left amygdala-right middle frontal gyrus (orbital part) rsFC was negatively correlated with NGASR in the SA group, but not the severity of depressive or anxiety symptoms. Using frontolimbic rsFCs as features, the SVMs obtained an overall 84% classification accuracy in distinguishing SA and NSA. A significant correlation was observed between the SVMs-predicted NGASR and clinical assessed NGASR (r = 0.51, p = 0.001). Our results demonstrated that decreased rsFCs in the frontolimbic system might be critical objective features of suicidality in BD-II patients, and could be useful for objective prediction of suicidality risk in individuals.

Aberrant functional connectivity and graph properties in bipolar II disorder with suicide attempts.

OBJECTIVE: The physiological mechanism of suicide attempt (SA) in bipolar II disorder (BD-II) remains only partially understood. The study seeks to identify the dysfunction pattern in suicide brain for BD-II patients. METHODS: Graph theory was utilized to explore topological properties at whole-brain, module and region levels based on resting-state functional MRI (rs-fMRI) data, which acquired from 38 un-medicated BD-II patients with at least one SA, 60 none SA (NSA) patients and 69 healthy controls (HCs). Finally, the correlation relationship between graph metrics and clinical variables were estimated. RESULTS: Compared with NSA patients and HCs, the functional connectivity strength between limbic/sub-cortical (LIMB/SubC) and frontoparietal network (FPN) were significantly weakened. Nodal strength in left head of caudate nucleus (HCN), raphe nucleus (RN), right nucleus accumbens (NAcc), right subgenual anterior cingulate cortex (sgACC) and nodal efficiency in right sgACC, right HCN for SA patients were significantly reduced relative to NSA and HCs. In particular, nodal strength in RN and nodal efficiency in right sgACC showed a significant negative correlation with Nurses' Global Assessment of Suicide Risk (NGASR) scores. LIMITATIONS: This is a single-mode cross-sectional study, the results were not verified by multi-center data. CONCLUSIONS: The abnormal disrupted FC between LIMB/SubC and FPN is associated with SA in BD-II patients, which increased the susceptibility of suicide. Especially, the dysfunction in RN and right sgACC predict a higher suicide risk in BD-II patients.The results can help us to understand the suicide mechanism and early judgment of suicidal behaviors for BD-II patients.

Structural-functional decoupling predicts suicide attempts in bipolar disorder patients with a current major depressive episode.

Bipolar disorder (BD) is associated with a high risk of suicidality, and it is challenging to predict suicide attempts in clinical practice to date. Although structural and functional connectivity alterations from neuroimaging studies have been previously reported in BD with suicide attempts, little is known about how abnormal structural and functional connectivity relates to each other. Here, we hypothesize that structure connectivity constrains functional connectivity, and structural-functional coupling is a more sensitive biomarker to detect subtle brain abnormalities than any single modality in BD patients with a current major depressive episode who had attempted suicide. By investigating structural and resting-state fMRI connectivity, as well as their coupling among 191 BD depression patients with or without a history of suicide attempts and 113 healthy controls, we found that suicide attempters in BD depression patients showed significantly decreased central-temporal structural connectivity, increased frontal-temporal functional connectivity, along with decreased structural-functional coupling compared with non-suicide attempters. Crucially, the altered structural connectivity network predicted the abnormal functional connectivity network profile, and the structural-functional coupling was significantly correlated with suicide risk but not with depression or anxiety severity. Our findings suggest that the structural connectome is the key determinant of brain dysfunction, and structural-functional coupling could serve as a valuable trait-like biomarker for BD suicidal predication over and above the intramodality network connectivity. Such a measure can have clinical implications for early identification of suicide attempters with BD depression and inform strategies for prevention.

Antidepressants normalize brain flexibility associated with multi-dimensional symptoms in major depressive patients.

BACKGROUND: The fundamental pathophysiology of major depressive disorder (MDD) could be characterized by functional brain networks which tightly and dynamically connect into groups as communities, making the flexible brain possible to external multifarious demands. We aim to scrutinize what brain dynamics go awry in MDD and antidepressants effects on multi-dimensional symptoms. METHODS: Thirty-five patients and thirty-five controls underwent resting-state functional magnetic resonance imaging (MRI). Patients were scanned before and after 8 or 12 weeks of pharmacotherapy. Group independent component analysis decomposed resting-state images to instinct networks and networks' integrated flexibility was calculated. Network flexibility between patients at baseline and after therapy were compared. RESULTS: All patients completed the clinical trial and MRI scans. Following antidepressants treatment, we found significant normalization of reduced network flexibility in default mode network (DMN) and cognitive control network (CCN) of MDD patients. Selectively significant correlations between network flexibility and multi-dimensional symptoms such as anxiety/somatization and hysteresis factor were also found. CONCLUSIONS: "Hypoflexible" CCN may involve in anxiety syndrome. Low flexibility in DMN may be indicative of hysteresis. These suggest an important pathophysiology of depressive manifestation of MDD. The antidepressant-induced normalization of the "hypoflexibility" suggests a selective pathway through which antidepressants may alleviate symptoms in depression.