Adolescent Major Depressive Disorder Patients Research Articles

Multimodal neuroimaging network associated with executive function in adolescent major depressive disorder patients via cognition-guided magnetic resonance imaging fusion.

Adolescents are high-risk population for major depressive disorder. Executive dysfunction emerges as a common feature of depression and exerts a significant influence on the social functionality of adolescents. This study aimed to identify the multimodal co-varying brain network related to executive function in adolescent with major depressive disorder. A total of 24 adolescent major depressive disorder patients and 43 healthy controls were included and completed the Intra-Extra Dimensional Set Shift Task. Multimodal neuroimaging data, including the amplitude of low-frequency fluctuations from resting-state functional magnetic resonance imaging and gray matter volume from structural magnetic resonance imaging, were combined with executive function using a supervised fusion method named multimodal canonical correlation analysis with reference plus joint independent component analysis. The major depressive disorder showed more total errors than the healthy controls in the Intra-Extra Dimensional Set Shift task. Their performance on the Intra-Extra Dimensional Set Shift Task was negatively related to the 14-item Hamilton Rating Scale for Anxiety score. We discovered an executive function-related multimodal fronto-occipito-temporal network with lower amplitude of low-frequency fluctuation and gray matter volume loadings in major depressive disorder. The gray matter component of the identified network was negatively related to errors made in Intra-Extra Dimensional Set Shift while positively related to stages completed. These findings may help to deepen our understanding of the pathophysiological mechanisms of cognitive dysfunction in adolescent depression.

Vulnerable brain regions in adolescent major depressive disorder: A resting-state functional magnetic resonance imaging activation likelihood estimation meta-analysis.

Adolescent major depressive disorder (MDD) is a significant mental health concern that often leads to recurrent depression in adulthood. Resting-state functional magnetic resonance imaging (rs-fMRI) offers unique insights into the neural mechanisms underlying this condition. However, despite previous research, the specific vulnerable brain regions affected in adolescent MDD patients have not been fully elucidated. To identify consistent vulnerable brain regions in adolescent MDD patients using rs-fMRI and activation likelihood estimation (ALE) meta-analysis. We performed a comprehensive literature search through July 12, 2023, for studies investigating brain functional changes in adolescent MDD patients. We utilized regional homogeneity (ReHo), amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) analyses. We compared the regions of aberrant spontaneous neural activity in adolescents with MDD vs healthy controls (HCs) using ALE. Ten studies (369 adolescent MDD patients and 313 HCs) were included. Combining the ReHo and ALFF/fALFF data, the results revealed that the activity in the right cuneus and left precuneus was lower in the adolescent MDD patients than in the HCs (voxel size: 648 mm3, P < 0.05), and no brain region exhibited increased activity. Based on the ALFF data, we found decreased activity in the right cuneus and left precuneus in adolescent MDD patients (voxel size: 736 mm3, P < 0.05), with no regions exhibiting increased activity. Through ALE meta-analysis, we consistently identified the right cuneus and left precuneus as vulnerable brain regions in adolescent MDD patients, increasing our understanding of the neuropathology of affected adolescents.

Abnormal intrinsic brain functional network dynamics in first-episode drug-naïve adolescent major depressive disorder.

Alterations in brain functional connectivity (FC) have been frequently reported in adolescent major depressive disorder (MDD). However, there are few studies of dynamic FC analysis, which can provide information about fluctuations in neural activity related to cognition and behavior. The goal of the present study was therefore to investigate the dynamic aspects of FC in adolescent MDD patients. Resting-state functional magnetic resonance imaging data were acquired from 94 adolescents with MDD and 78 healthy controls. Independent component analysis, a sliding-window approach, and graph-theory methods were used to investigate the potential differences in dynamic FC properties between the adolescent MDD patients and controls. Three main FC states were identified, State 1 which was predominant, and State 2 and State 3 which occurred less frequently. Adolescent MDD patients spent significantly more time in the weakly-connected and relatively highly-modularized State 1, spent significantly less time in the strongly-connected and low-modularized State 2, and had significantly higher variability of both global and local efficiency, compared to the controls. Classification of patients with adolescent MDD was most readily performed based on State 1 which exhibited disrupted intra- and inter-network FC involving multiple functional networks. Our study suggests local segregation and global integration impairments and segregation-integration imbalance of functional networks in adolescent MDD patients from the perspectives of dynamic FC. These findings may provide new insights into the neurobiology of adolescent MDD.

Plasma alpha-trypsin inhibitor heavy chain 4 as an age-specific biomarker in the diagnosis and treatment of major depressive disorder.

The diagnosis of major depressive disorder (MDD) mainly depends on subjective clinical symptoms, without an acceptable objective biomarker for the clinical application of MDD. Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) showed a high specificity as biomarker for the diagnosis and treatment of MDD. The present study aimed to investigate differences in plasma ITIH4 in two different aged MDD patients and underlying pathological mechanisms of plasma ITIH4 in the occurrence and development of MDD. Sixty-five adult MDD patients, 51 adolescent MDD patients, and 64 healthy controls (HCs) were included in the present study. A 14-days' antidepressive treatment was conducted in all MDD patients. Psychological assessments were performed and plasma ITIH4 and astrocyte-related markers were detected for all participants. (1) Plasma levels of ITIH4 in adult MDD patients were significantly higher than adolescent MDD patients and HCs, and significantly increased plasma ITIH4 levels was observed in adolescent MDD patients compared with HCs (2). There were positive correlations between plasma ITIH4 levels and 24-item Hamilton Depression Scale (HAMD-24) scores and plasma glial fibrillary acidic protein (GFAP) levels in MDD patients, however, plasma ITIH4 levels were significantly correlated with age just in adult MDD patients (3). Plasma ITIH4 showed area under the curve values of 0.824 and 0.729 to differentiate adult MDD patients and adolescent MDD patients from HCs, respectively (4). There was significant decrease in plasma levels of ITIH4 between before and after antidepressive treatment in adult MDD patients, but not in adolescent MDD patients (5). Changed value of ITIH4 levels were correlated with the changed value of GFAP levels and changed rate of HAMD-24 scores in adult MDD patients following antidepressive treatment. Plasma ITIH4 may be potential plasma biomarkers of MDD with age-related specificity, which was associated with depressive symptoms astrocyte-related pathologic changes, and antidepressive treatment efficacy.

Altered single-subject gray matter structural networks in first-episode drug-naïve adolescent major depressive disorder

Although previous studies have demonstrated regional gray matter (GM) structural abnormalities in adolescents with major depressive disorder (MDD), how the topological organization of GM networks is affected in these patients is still unclear. Structural magnetic resonance imaging data were acquired from 100 first-episode drug-naïve adolescent MDD patients and 80 healthy controls (HCs). Whole-brain GM structural network was constructed for each subject, and a graph theory analysis was used to calculate the topological metrics of GM networks. Adolescent MDD patients showed significantly lower cluster coefficient and local efficiency compared to HCs. Compared to controls, adolescent MDD patients showed higher nodal centralities in the bilateral cuneus, left lingual gyrus, and right middle occipital gyrus and lower nodal centralities in the bilateral dorsolateral superior frontal gyrus, bilateral middle frontal gyrus, right anterior cingulate and paracingulate gyri, bilateral hippocampus, bilateral amygdala, bilateral caudate nucleus, and bilateral thalamus. Nodal centralities of the hippocampus were negatively associated with symptom severity and illness duration. Our findings suggest disrupted topological organization of GM structural networks in adolescent MDD patients. Impaired local segregation and abnormal nodal centralities in the prefrontal-subcortical-limbic areas and visual cortex regions may play important roles in the neurobiology of adolescent-onset MDD.

Childhood trauma is linked to abnormal static-dynamic brain topology in adolescents with major depressive disorder

Childhood trauma is a leading risk factor for adolescents developing major depressive disorder (MDD); however, the underlying neuroimaging mechanisms remain unclear. This study aimed to investigate the association among childhood trauma, MDD and brain dysfunctions by combining static and dynamic brain network models. We recruited 46 first-episode drug-naïve adolescent MDD patients with childhood trauma (MDD-CT), 53 MDD patients without childhood trauma (MDD-nCT), and 90 healthy controls (HCs) for resting-state functional magnetic resonance imaging (fMRI) scans; all participants were aged 13–18 years. Compared to the HCs and MDD-nCT groups, the MDD-CT group exhibited significantly higher global and local efficiency in static brain networks and significantly higher temporal correlation coefficients in dynamic brain network models at the whole-brain level, and altered the local efficiency of default mode network (DMN) and temporal correlation coefficients of DMN, salience (SAN), and attention (ATN) networks at the local perspective. Correlation analysis indicated that altered brain network features and clinical symptoms, childhood trauma, and particularly emotional neglect were highly correlated in adolescents with MDD. This study may provide new evidence for the dysconnectivity hypothesis regarding the associations between childhood trauma and MDD in adolescents from the perspectives of both static and dynamic brain topology.

The amplitude of low-frequency fluctuation characteristics in depressed adolescents with suicide attempts: a resting-state fMRI study.

The amplitude of low-frequency fluctuation (ALFF) is a measure of spontaneous brain activity derived from resting-state functional magnetic resonance imaging (rs-fMRI). Previous research has suggested that abnormal ALFF values may be associated with major depressive disorder (MDD) and suicide attempts in adolescents. In this study, our aim was to investigate the differences in ALFF values between adolescent MDD patients with and without a history of suicide attempts, and to explore the potential utility of ALFF as a neuroimaging biomarker for aiding in the diagnosis and prediction of suicide attempts in this population. The study included 34 adolescent depression patients with suicide attempts (SU group), 43 depression patients without suicide attempts (NSU group), and 36 healthy controls (HC group). Depression was diagnosed using a threshold score greater than 17 on the Hamilton Depression Rating Scale (HDRS). The rs-fMRI was employed to calculate zALFF values and compare differences among the groups. Associations between zALFF values in specific brain regions and clinical variables such as emotion regulation difficulties were explored using Pearson partial correlation analysis. Receiver-Operating Characteristics (ROC) analysis assessed the ability of mean zALFF values to differentiate between SU and NSU groups. Significant differences in zALFF values were observed in the left and right inferior temporal gyrus (l-ITG, r-ITG) and right fusiform gyrus (r-FG) among the three groups (GRF corrected). Both SU and NSU groups exhibited increased zALFF values in the inferior temporal gyrus compared to the HC group. Furthermore, the SU group showed significantly higher zALFF values in the l-ITG and r-FG compared to both the NSU group and the HC group. Partial correlation analysis revealed a negative correlation between zALFF values in the left superior and middle frontal gyrus (l-SFG, l-MFG) and the degree of emotional dysregulation in the SU group (R = -0.496, p = 0.003; R = -0.484, p = 0.005). Combining zALFF values from the l-ITG and r-FG achieved successful discrimination between depressed adolescents with and without suicide attempts (AUC = 0.855) with high sensitivity (86%) and specificity (71%). Depressed adolescents with suicidal behavior exhibit unique neural activity patterns in the inferior temporal gyrus and fusiform gyrus. These findings highlight the potential utility of these specific brain regions as biomarkers for identifying suicide risk in depressed adolescents. Furthermore, associations between emotion dysregulation and activity in their frontal gyrus regions were observed. These findings provide preliminary yet pertinent insights into the pathophysiology of suicide in depressed adolescents.

Prediction of early improvement of major depressive disorder to antidepressant medication in adolescents with radiomics analysis after ComBat harmonization based on multiscale structural MRI

BackgroundDue to individual differences and lack of objective biomarkers, only 30-40% patients with major depressive disorder (MDD) achieve remission after initial antidepressant medication (ADM). We aimed to employ radiomics analysis after ComBat harmonization to predict early improvement to ADM in adolescents with MDD by using brain multiscale structural MRI (sMRI) and identify the radiomics features with high prediction power for selection of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).Methods121 MDD patients were recruited for brain sMRI, including three-dimensional T1 weighted imaging (3D-T1WI)and diffusion tensor imaging (DTI). After receiving SSRIs or SNRIs for 2 weeks, the subjects were divided into ADM improvers (SSRIs improvers and SNRIs improvers) and non-improvers according to reduction rate of the Hamilton Depression Rating Scale, 17 item (HAM-D17) score. Then, sMRI data were preprocessed, and conventional imaging indicators and radiomics features of gray matter (GM) based on surface-based morphology (SBM) and voxel-based morphology (VBM) and diffusion properties of white matter (WM) were extracted and harmonized with ComBat harmonization. Two-level reduction strategy with analysis of variance (ANOVA) and recursive feature elimination (RFE) was utilized sequentially to decrease high-dimensional features. Support vector machine with radial basis function kernel (RBF-SVM) was used to integrate multiscale sMRI features to construct models for early improvement prediction. Area under the curve (AUC), accuracy, sensitivity, and specificity based on the leave-one-out cross-validation (LOO-CV) and receiver operating characteristic (ROC) curve analysis were calculated to evaluate the model performance. Permutation tests were used for assessing the generalization rate.ResultsAfter 2-week ADM, 121 patients were divided into 67 ADM improvers (31 SSRIs improvers and 36 SNRIs improvers) and 54 ADM non-improvers. After two-level dimensionality reduction, 8 conventional indicators (2 VBM-based features and 6 diffusion features) and 49 radiomics features (16 VBM-based features and 33 diffusion features) were selected. The overall accuracy of RBF-SVM models based on conventional indicators and radiomics features was 74.80% and 88.19%. The radiomics model achieved the AUC, sensitivity, specificity, and accuracy of 0.889, 91.2%, 80.1% and 85.1%, 0.954, 89.2%, 87.4% and 88.5%, 0.942, 91.9%, 82.5% and 86.8% for predicting ADM improvers, SSRIs improvers and SNRIs improvers, respectively. P value of permutation tests were less than 0.001. The radiomics features predicting ADM improver were mainly located in the hippocampus, medial orbitofrontal gyrus, anterior cingulate gyrus, cerebellum (lobule vii-b), body of corpus callosum, etc. The radiomics features predicting SSRIs improver were primarily distributed in hippocampus, amygdala, inferior temporal gyrus, thalamus, cerebellum (lobule vi), fornix, cerebellar peduncle, etc. The radiomics features predicting SNRIs improver were primarily located in the medial orbitofrontal cortex, anterior cingulate gyrus, ventral striatum, corpus callosum, etc.ConclusionsThese findings suggest the radiomics analysis based on brain multiscale sMRI after ComBat harmonization could effectively predict the early improvement of ADM in adolescent MDD patients with a high accuracy, which was superior to the model based on the conventional indicators. The radiomics features with high prediction power may help for the individual selection of SSRIs and SNRIs.

Co-expression network of mRNA and DNA methylation in first-episode and drug-naive adolescents with major depressive disorder.

We explored the DNA methylation and messenger RNA (mRNA) co-expression network and hub genes in first-episode, drug-naive adolescents with major depressive disorder (MDD). To preliminarily explore whether adolescent MDD has unique mechanisms compared with adult MDD. We compared DNA methylation and mRNA profiles of peripheral blood mononuclear cells from four first-episode and drug-naive adolescents with MDD and five healthy adolescent controls (HCs). We performed differential expression analysis, constructed co-expression network, and screened the hub genes. And enrichment analysis was performed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We also downloaded DNA methylation and mRNA datasets of adults with MDD (GSE113725/GSE38206) from the GEO database, and performed differential expression and enrichment analysis. Our clinical data showed that 3034 methylation sites and 4190 mRNAs were differentially expressed in first-episode, drug-naive adolescents MDD patients compared with HCs. 19 hub genes were screened out according to the high degree value in the co-expression network. The results from the GEO database showed that compared with adult HCs, there were 290 methylation sites and 127 mRNAs were differentially expressed in adult MDD patients. Compared with adolescent HCs and adult MDD patients, the DNA methylation and mRNA expression patterns of first-episode, drug-naive adolescent MDD patients were different. The co-expression network of DNA methylation and mRNA and the screened hub genes may play an important role in the pathogenesis of MDD in first-episode, drug-naive adolescents. Compared with adult MDD, adolescent MDD is more enriched in metabolism in terms of function and pathways.

Resting-state functional magnetic resonance imaging-based identification of altered brain the fractional amplitude of low frequency fluctuation in adolescent major depressive disorder patients undergoing electroconvulsive therapy.

PurposeWhile electroconvulsive therapy (ECT) has been repeatedly been shown to effectively and efficiently treat the major depressive disorder (MDD), the mechanistic basis for such therapeutic efficacy remains to be firmly established. As such, further research exploring the ECT-based treatment of MDD in an adolescent population is warranted.MethodsThis study included 30 treatment-naïve first-episode MDD patients and 30 healthy control (HC) individuals (aged 12–17 years). All participants were scanned using rs-fMRI, and the 30 MDD patients were scanned again after 2 weeks of the ECT treatment period. Intrinsic local activity in each voxel was assessed based on the fractional amplitude of low frequency fluctuation (fALFF) parameter, with all fALFF analyses being completed using the REST application. Correlations between ECT-related changes in fALFF and clinical parameters were additionally examined.ResultsRelative to HCs, MDD patients exhibited increased fALFF values in the right inferior frontal gyrus (ORBinf), inferior occipital gyrus (IOG), and the left middle frontal gyrus (MFG) at baseline. Following ECT, these patients exhibited significant increases in fALFF values in the right medial superior frontal gyrus (SFGmed), dorsolateral superior frontal gyrus (SFGdor), anterior cingulate, and paracingulate gyrus (ACG), median cingulate and paracingulate gyrus (DCG), and left MFG. MDD patient HAMD scores were negatively correlated with fALFF values when analyzing pre-ECT vs. post-HCT ΔHAMD and fALFF values in the right SFGmed, SFGdor, and the left MFG.ConclusionThese data suggest that ECT induced altered fALFF in some regions of the brain, suggesting that these alterations may serve as a neurobiological indicator of ECT effectiveness in MDD adolescents.

Disturbance of neurotransmitter metabolism in drug-naïve, first-episode major depressive disorder: a comparative study on adult and adolescent cohorts.

Neurotransmitter metabolism plays a critical role in the pathophysiology of major depressive disorder (MDD). However, whether the neurotransmitter metabolism in adolescent MDD is differentiated from adult MDD is still elusive. In the current study, plasma concentrations of monoamine and amino acid neurotransmitters as well as their metabolites, including tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), vanillylmandelic acid (VMA), 3-methoxy-4-hydroxyphenylglycol (MHPG), glutamine (GLN), glutamate (GLU) and gamma-aminobutyric acid (GABA), were measured and compared in two cohorts of subjects (adult cohort: 31 first-episode MDD vs. 35 healthy controls; adolescent cohort: 33 first-episode MDD vs. 30 healthy controls). To assess the effects of antidepressant treatment, we also analyzed the concentrations of these indexes pre- and post-treatment in adult and adolescent cohorts. At baseline, the deficits of neurotransmitter metabolism in adult MDD were manifested in all the neurotransmitter systems. In contrast, for adolescent MDD, the dysregulation of neurotransmission was mainly indicated in the catecholaminergic systems. After antidepressant treatment, adult MDD showed increased TRP, KYN, KYNA and GLU levels, together with decreased levels of 5-HIAA and DOPAC. Adolescent MDD illustrated an increased level of 5-HT and decreased levels of TRP and GABA. The improvements of Hamilton total scores correlated with the changes in plasma TRP and the turnover of KYN/TRP after treatment in all MDD patients. However, these correlations were only manifested in the adult MDD rather than in adolescent MDD patients. The findings highlight the shared and distinguished neurotransmitter pathways in MDD and emphasize the different antidepressant responses between adults and adolescents. Potentially, the neurotransmitters above could serve as diagnostic biomarkers and provide a novel pharmacological treatment strategy for MDD.

Associations between childhood chronic stress and dynamic functional connectivity in drug-naïve, first-episode adolescent MDD

BackgroundWe explored the associations between chronic stress and dynamic working patterns of the whole brain using resting state MRI data in drug-naïve, first-episode adolescents with major depressive disorder (MDD). MethodsWe compared dynamic functional connectivity (dyn-FC) and screen out networks with difference in whole brain between 45 healthy controls (HC) and 60 adolescent MDD patients using dynamic independent components analysis. In each of these networks with difference between groups, hub brain regions were selected as functionally connected to more than 30 brain regions at the same time. Then we extracted the dyn-FC coefficients of each hub brain region with other brain regions in each component at different time points and calculated the average value of the entire scan time. Finally, we explored correlations between these average values of the entire scan time and scores on the Childhood Chronic Stress Questionnaire (CCSQ). ResultsWe found three networks as well as some hub brain regions with different dyn-FC patterns between adolescent MDD and HC. Scores on the CCSQ were found to correlate with dynamic FC between hub brain areas and certain other brain areas in MDD patients. Limitationsour cross-sectional study design does not allow us to speculate about causality between chronic stress and depression. Prospective cohort studies should explore in detail how the changes in dynamic FC appear and evolve during MDD. ConclusionsChronic stress is related with the brain dynamic working patterns in adolescent MDD.

Identification of suicidality in adolescent major depressive disorder patients using sMRI: A machine learning approach.

Background: Suicidal behavior is a major concern for patients who suffer from major depressive disorder (MDD), especially among adolescents and young adults. Machine learning models with the capability of suicide risk identification at an individual level could improve suicide prevention among high-risk patient population.Methods: A cross-sectional assessment was conducted on a sample of 66 adolescents/young adults diagnosed with MDD. The structural T1-weighted MRI scan of each subject was processed using the FreeSurfer software. The classification model was conducted using the Support Vector Machine - Recursive Feature Elimination (SVM-RFE) algorithm to distinguish suicide attempters and patients with suicidal ideation but without attempts.Results: The SVM model was able to correctly identify suicide attempters and patients with suicidal ideation but without attempts with a cross-validated prediction balanced accuracy of 78.59%, the sensitivity was 73.17% and the specificity was 84.0%. The positive predictive value of suicide attempt was 88.24%, and the negative predictive value was 65.63%. Right lateral orbitofrontal thickness, left caudal anterior cingulate thickness, left fusiform thickness, left temporal pole volume, right rostral anterior cingulate volume, left lateral orbitofrontal thickness, left posterior cingulate thickness, right pars orbitalis thickness, right posterior cingulate thickness, and left medial orbitofrontal thickness were the 10 top-ranked classifiers for suicide attempt.Conclusions: The findings indicated that structural MRI data can be useful for the classification of suicide risk. The algorithm developed in current study may lead to identify suicide attempt risk among MDD patients.

The changes of amplitude of low frequency fluctuation in adolescent depression patients with suicidal ideation: a resting-state functional magnetic resonance imaging study

Objective To investigate the changes of brain activity in adolescents with first-episode major depressive disorder (MDD) and its significance. Methods Totally 42 first-episode MDD patients with suicidal ideation (SU group), 17 MDD patients without suicidal ideation (NSU group) and 29 healthy controls (HC group) were examined by psychological assessment and resting-state functional magnetic resonance imaging (fMRI). The differences of brain functional activities between the three groups were compared by amplitude of low frequency fluctuation(ALFF). The relationship between the difference of zALFF value in brain regions and the severity of depression, intensity of suicidal ideation were further analyzed. Results The zALFF values in the left hippocampus(MNI: x=-21, y=-33, z=0) and left Frontal_Sup_Medial(MNI: x=3, y=33, z=63) of the three groups were significantly abnormal (P 20, uncorrected). The results of Post-hoc test showed that the zALFF value of left hippocampus increased significantly (F=28.931) and decreased significantly in left Frontal_Sup_Medial(F=16.648)in SU group , compared with NSU group and HC group(P 0.05). In SU group, the zALFF values of left hippocampus and left Frontal_Sup_Medial were not correlated with total scores of HAMD-24(r=-0.214, -0.103) and suicide ideation intensity factor scores(r=0.115, -0.055)(P>0.05). Conclusion Abnormal autonomic nervous activity exists in left hippocampus and left Frontal_Sup_Medial in adolescent MDD patients with suicidal ideation, which may be the neurological basis and biological index of suicidal ideation. Key words: Major depressive disorder; Suicidal ideation; Adolescents; Amplitude of low frequency fluctuation

White matter disturbances in major depressive disorder: a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group

Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12–88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen’s d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen’s d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.

Resting-state functional connectivity in medication-naïve adolescents with major depressive disorder

Adolescence is a vulnerable period for major depressive disorder (MDD). The aim of our study was to investigate resting-state functional connectivity (RSFC) in first-episode, medication-naïve adolescent MDD patients. Twenty-three drug-naïve adolescents diagnosed with first-episode MDD and 27 healthy participants were enrolled. Seed-to-voxel RSFC analyses were performed. The frontolimbic circuit regions of interest included the amygdala, anterior cingulate cortex, insula, and hippocampus. A correlation analysis between the RSFC and Children's Depression Inventory, Hamilton depression rating scale, and duration of episodes was performed. The adolescents with MDD exhibited the following characteristics: a lower RSFC between the right amygdala and right superior frontal gyrus; a lower RSFC between the right hippocampus and clusters including the right insula and right middle frontal gyrus; a higher RSFC between the left insula and clusters including the bilateral middle frontal gyrus, right superior frontal gyrus, and right frontal pole; and a higher RSFC between the left dorsal anterior cingulate cortex and a cluster including the left insula. Medication-naïve adolescents with depression display lower connectivity of several brain regions implicated in processing, regulation, and memory of emotions. Higher connectivity was observed in brain regions that potentially explain rumination, impaired concentration, and physiological arousal.

Complex cardiac vagal regulation to mental and physiological stress in adolescent major depression

BackgroundCardiovagal control is known to be reduced in major depressive disorder (MDD), however, the neurocardiac reflex control to distinct types of stressors is still unclear. We aimed to study parasympathetically mediated cardiac reflex functioning in response to mental and physiological stressors using heart rate variability (HRV) linear and nonlinear analysis in adolescent MDD. MethodsWe examined 60 adolescents (40 girls) with MDD (age 14.9 ± 0.3 years) and 60 age and gender-matched controls. ECG was continuously recorded during stress protocol: baseline, Go/NoGo test, recovery, supine position, and orthostasis. Evaluated HRV linear and nonlinear indices: RR interval, pNN50, rMSSD, HF-HRV, Poincaré plot (SD1), symbolic dynamics 2UV%. Cardiovagal reactivity expressed as percentual change (%) was calculated in response to both stressors. ResultsIn each phase of stress protocol, the MDD group had significantly reduced HRV parameters compared to controls, except for symbolic dynamics index 2UV% in supine position. The reactivity of HRV indices was significantly greater in response to orthostasis in MDD compared to controls. No significant differences were found in response to Go/NoGo test. LimitationsThe smoking status and the menstrual cycle phase potentially affecting the HRV parameters were not monitored. Future research is needed to expand a sample size with respect to sex and to study neurocardiac response to other different stressors in MDD. ConclusionsThis study revealed reduced resting cardiovagal regulation and greater vagal withdrawal indicating abnormal neurocardiac reflex functioning to physiological stressor (orthostasis) in adolescent MDD patients. Nonlinear HRV analysis was sensitive to detect cardiac-linked regulatory differences in adolescent depression.

Abnormal amygdala resting-state functional connectivity in adults and adolescents with major depressive disorder: A comparative meta-analysis.

BackgroundAlthough dysfunction of amygdala-related circuits is centrally implicated in major depressive disorder (MDD), little is known about how this dysfunction differs between adult and adolescent MDD patients.MethodsVoxel-wise meta-analyses of abnormal amygdala resting-state functional connectivity (rsFC) were conducted in adult and adolescent groups separately, followed by a quantitative meta-analytic comparison of the two groups.FindingsNineteen studies that included 665 MDD patients (392 adults and 273 adolescents) and 546 controls (341 adults and 205 adolescents) were identified in the current study. Adult-specific abnormal amygdala rsFC in MDD patients compared to that in controls was located mainly within the affective network, including increased connectivity with the right hippocampus/parahippocampus and bilateral ventromedial orbitofrontal cortex and decreased connectivity with the bilateral insula and the left caudate. Adolescent MDD patients specifically demonstrated decreased amygdala rsFC within the cognitive control network encompassing the left dorsolateral prefrontal cortex and imbalanced amygdala rsFC within the default mode network, which was manifested as hyperconnectivity in the right precuneus and hypoconnectivity in the right inferior temporal gyrus. Additionally, direct comparison between the two groups showed that adult patients had strengthened amygdala rsFC with the right hippocampus/parahippocampus as well as the right inferior temporal gyrus and weakened amygdala rsFC with the bilateral insula compared to that in adolescent patients.InterpretationDistinct impairments of amygdala-centered rsFC in adult and adolescent patients were related to different network dysfunctions in MDD. Adult-specific amygdala rsFC dysfunction within the affective network presumably reflects emotional dysregulation in MDD, whereas adolescent-specific amygdala rsFC abnormalities in networks involved in cognitive control might reflect the neural basis of affective cognition deficiency that is characteristic of adolescent MDD.FundThis study was supported by a grant from the National Natural Science Foundation of China (81671669) and by a Sichuan Provincial Youth Grant (2017JQ0001).

Abnormal changes of functional connectivity between anterior cingulate cortex and amygdala in adolescents patients with first-episode depression

Objective To study the resting-state functional connectivity(FC) changes of anterior cingulate cortex(ACC) and amygdala in adolescent patients with medication-naive first-episode major depressive disorder(MDD). Methods Medication-naive first-episode MDD adolescents(n=30) and pair-wise matched healthy controls(HCs, n=29) underwent resting-state functional magnetic resonance images(fMRI). To study whether there were different in FC changes between amygdala and ACC and whole brain regions, and whether abnormal FC was related to clinical characteristics. Results Compared with HCs, the adolescent MDD patients showed decreased FC between the left amygdala and right thalamus(MNI x, y, z: 15, -21, 18)(t=-2.85)and increased FC between the left amygdala and the bilateral temporal middle gyrus, left occipital gyrus, right medial prefrontal cortex(MPFC)(MNI x, y, z: 9, 66, 15)(t=2.80). The right amygdale showed decreased FC with bilateral middle frontal gyrus, left caudate(MNI x, y, z: -15, -9, 21)(t=-2.53), right thalamus(MNI x, y, z: 12, -36, 12)(t=-3.01), right cerebellum(MNI x, y, z: 3, -84, -33)(t=-2.45) and increased FC with right temporal middle gyrus, right MPFC(MNI x, y, z: 6, 69, 12)(t=2.41). The left ACC showed decreased FC with left cerebellum(MNI x, y, z: 12, -87, -24)(t=-2.36), left frontal inferior triangle gyrus, right frontal inferior orbital gyrus and increased FC with right frontal middle orbital gyrus.The right ACC showed decreased FC with left caudate(MNI x, y, z: -15, 21, 6)(t=-2.29), right temporal middle gyrus, right MPFC(MNI x, y, z: 9, 54, 36)(t=-2.29), right frontal inferior orbital gyrus, right angular(MNI x, y, z: 45, -51, 21)(t=-3.01), left dorsolateral prefrontal cortex(MNI x, y, z: -21, 33, 36)(t=-2.61). The increased FC between the left amygdale and bilateral temporal middle gyrus showed positive correlation with the score of HAMD(r=0.50, P<0.05; r=0.45, P<0.05). And the FC between the right amygdale and right middle frontal gyrus was positive correlation with duration of disease(r=0.63, P<0.05). Conclusion There is widespread FC disorder in amygdala and ACC in adolescents patients with first-episode depression.Abnormal FC changes may be the neuropathological mechanism of depression. Key words: Adolescent major depressive disorder; Resting-state fMRI; Functional connectivity; Amygdala; Anterior cingulated cortex

Dysfunctional resting-state connectivity of default mode network in adolescent patients with first-episode drug-naive major depressive disorder

Objective: To study resting-state functional connectivity (FC) of default mode network (DMN) in adolescent patients with first-episode drug-naive major depressive disorder (MDD). Methods: We enrolled thirty first-episode and drug-naive adolescent MDD patients and twenty-nine adolescent healthy control (HC) participants in the First Affiliated Hospital of Zhengzhou University. There were no differences in age, sex, and education between the MDD and HC group. Resting-state functional magnetic resonance images (fMRI) was performed. We selected posterior cingulate cortex (PCC) and medial prefrontal cortex (MPFC) of DMN as regions of interests (ROI). The differences of these regions from the whole brain functional connectivity were analyzed. The relations between abnormalities in FCs of DMN and clinical variables were further investigated. Results: Compared to the HCs, the MDD patients had congruently reduced FCs between the PCC and cerebellum, temporal cortices, occipital cortices, fusiform, dorsolateral prefrontal cortex. MPFC not only had reduced FCs with fusiform, temporal cortices, anterior cingulate cortex, but also had enhanced FCs with occipital cortices, parietal cortices, and precentral gyrus. In addition, the increased FC between the right MPFC and right precentral gyrus was positive correlated with Hamilton Rating Scale for Depression (HAMD) scores (r=0.38, P=0.04). The reduced FC between the left middle temporal gyrus and left PCC as well as the enhanced FC between the right middle cingulum and right MPFC were positive correlated with the duration of depression since onset (r=0.39, P=0.03; r=0.38, P=0.04). Conclusions: These findings show dysfunctional DMN connectivity of adolescent MDD patients. Neurodevelopmental abnormalities in DMN may present in adolescent MDD.