Sex differences in aberrant functional connectivity of three core networks and subcortical networks in medication-free adolescent-onset major depressive disorder.

Major depressive disorder demonstrated sex differences in prevalence and symptoms, which were more pronounced during adolescence. Yet, research on sex-specific brain network characteristics in adolescent-onset major depressive disorder remains limited. This study investigated sex-specific and nonspecific alterations in resting-state functional connectivity of three core networks (frontoparietal network, salience network, and default mode network) and subcortical networks in adolescent-onset major depressive disorder, using seed-based resting-state functional connectivity in 50 medication-free patients with adolescent-onset major depressive disorder and 56 healthy controls. Irrespective of sex, compared with healthy controls, adolescent-onset major depressive disorder patients showed hypoconnectivity between bilateral hippocampus and right superior temporal gyrus (default mode network). More importantly, we further found that females with adolescent-onset major depressive disorder exhibited hypoconnectivity within the default mode network (medial prefrontal cortex), and between the subcortical regions (i.e. amygdala, striatum, and thalamus) with the default mode network (angular gyrus and posterior cingulate cortex) and the frontoparietal network (dorsal prefrontal cortex), while the opposite patterns of resting-state functional connectivity alterations were observed in males with adolescent-onset major depressive disorder, relative to their sex-matched healthy controls. Moreover, several sex-specific resting-state functional connectivity changes were correlated with age of onset, sleep disturbance, and anxiety in adolescent-onset major depressive disorder with different sex. These findings suggested that these sex-specific resting-state functional connectivity alterations may reflect the differences in brain development or processes related to early illness onset, underscoring the necessity for sex-tailored diagnostic and therapeutic approaches in adolescent-onset major depressive disorder.

Negative family and interpersonal relationship are associated with centromedial amygdala functional connectivity alterations in adolescent depression.

The amygdala, known for its functional heterogeneity, plays a critical role in the neural mechanism of adolescent major depressive disorder (aMDD). However, changes in its subregional functional networks in relation to stressful factors remain unclear. We recruited 78 comorbidity-free, medication-naive aMDD patients and 40 matched healthy controls (HC) to explore changes in resting-state functional connectivity (FC) across four amygdala subregions: the centromedial nucleus (CM), the basolateral nucleus (LB), the superficial nucleus (SF), and the amygdalostriatal transition area (Astr). Then, we performed partial correlation analysis to investigate the relationship between amygdala subregional FC and stressful factors as measured by the Chinese Version of Family Environment Scale (FES-CV) and the Adolescent Self-Rated Life Events Scale (ASLEC). Compared to HC, aMDD patients demonstrated significantly decreased functional connectivity between the left CM and left precentral gyrus, as well as between left SF and left precentral gyrus, and between left LB and posterior cingulate gyrus (PCC)/precuneus. In aMDD group, left CM-precentral gyrus FC exhibited negative correlation with interpersonal relationship and punishment, and positive correlation with family cohesion and expressiveness. This study reveals distinct patterns of abnormal functional connectivity among amygdala subregions in aMDD. Our findings suggest that the CM network, in particular, may be involved in stress-related factors in aMDD, which provide a potential target for the prevention and treatment of adolescent depression.

Divergent effects of sex on hippocampal subfield alterations in drug-naive patients with major depressive disorder.

BACKGROUND: The hippocampus is a crucial brain structure in etiological models of major depressive disorder (MDD). It remains unclear whether sex differences in the incidence and symptoms of MDD are related to differential illness-associated brain alterations, including alterations in the hippocampus. This study investigated divergent the effects of sex on hippocampal subfield alterations in drug-naive patients with MDD. METHODS: High-resolution structural MR images were obtained from 144 drug-naive individuals with MDD early in their illness course and 135 age- and sex-matched healthy controls (HCs). Hippocampal subfields were segmented using FreeSurfer software and analyzed in terms of both histological subfields (CA1-4, dentate gyrus, etc.) and more integrative larger functional subregions (head, body and tail). RESULTS: We observed a significant overall reduction in hippocampal volume in MDD patients, with deficits more prominent deficits in the posterior hippocampus. Differences in anatomic alterations between male and female patients were observed in the CA1-head, presubiculum-body and fimbria in the left hemisphere. Exploratory analyses revealed different patterns of clinical and memory function correlations with histological subfields and functional subregions between male and female patients primarily in the hippocampal head and body. LIMITATIONS: This cross-sectional study cannot clarify the causality of hippocampal alterations or their association with illness risk or onset. CONCLUSIONS: These findings represent the first reported sex-specific alterations in hippocampal histological subfields in patients with MDD early in the illness course prior to treatment. Sex-specific hippocampal alterations may contribute to diverse sex differences in the clinical presentation of MDD.

Multivariate association between psychosocial environment, behaviors, and brain functional networks in adolescent depression.

BACKGROUND: Adolescent depression shows high clinical heterogeneity. Brain functional networks serve as a powerful tool for investigating neural mechanisms underlying depression profiles. A key challenge is to characterize how variation in brain functional organization links to behavioral features and psychosocial environmental influences. METHODS: We recruited 80 adolescents with major depressive disorder (MDD) and 42 healthy controls (HCs). First, we estimated the differences in functional connectivity of resting-state networks (RSN) between the two groups. Then, we used sparse canonical correlation analysis to characterize patterns of associations between RSN connectivity and symptoms, cognition, and psychosocial environmental factors in MDD adolescents. Clustering analysis was applied to stratify patients into homogenous subtypes according to these brain-behavior-environment associations. RESULTS: MDD adolescents showed significantly hyperconnectivity between the ventral attention and cingulo-opercular networks compared with HCs. We identified one reliable pattern of covariation between RSN connectivity and clinical/environmental features in MDD adolescents. In this pattern, psychosocial factors, especially the interpersonal and family relationships, were major contributors to variation in connectivity of salience, cingulo-opercular, ventral attention, subcortical and somatosensory-motor networks. Based on this association, we categorized patients into two subgroups which showed different environment and symptoms characteristics, and distinct connectivity alterations. These differences were covered up when the patients were taken as a whole group. CONCLUSION: This study identified the environmental exposures associated with specific functional networks in MDD youths. Our findings emphasize the importance of the psychosocial context in assessing brain function alterations in adolescent depression and have the potential to promote targeted treatment and precise prevention.

Distinctive intrinsic functional connectivity alterations of anterior cingulate cortex subdivisions in major depressive disorder: A systematic review and meta-analysis.

Evidence of whether the intrinsic functional connectivity of anterior cingulate cortex (ACC) and its subregions is altered in major depressive disorder (MDD) remains inconclusive. A systematic review and meta-analysis were therefore performed on the whole-brain resting-state functional connectivity (rsFC) studies using the ACC and its subregions as seed regions in MDD, in order to draw more reliable conclusions. Forty-four ACC-based rsFC studies were included, comprising 25 subgenual ACC-based studies, 11 pregenual ACC-based studies, and 17 dorsal ACC-based studies. Specific alterations of rsFC were identified for each ACC subregion in patients with MDD, with altered rsFC of subgenual ACC in emotion-related brain regions, of pregenual ACC in sensorimotor-related regions, and of dorsal ACC in cognition-related regions. Furthermore, meta-regression analysis revealed a significant negative correlation between the pgACC-caudate hypoconnectivity and percentage of female patients in the study cohort. This meta-analysis provides robust evidence of altered intrinsic functional connectivity of the ACC subregions in MDD, which may hold relevance to understanding the origin of, and treating, the emotional, sensorimotor and cognitive dysfunctions that are often observed in these patients.

Suprachiasmatic nucleus functional connectivity related to insomnia symptoms in adolescents with major depressive disorder.

Background: Insomnia is a commonly seen symptom in adolescents with major depressive disorder (MDD). The suprachiasmatic nucleus (SCN), which is the circadian rhythm regulation center, plays a crucial role in the regulation of sleep-wake circulation. Nevertheless, how SCN function contributes to the exact neural mechanisms underlying the associations between insomnia and depressive symptoms has not been explored in adolescents. In the current study, we aimed to explore the relationship between SCN functional connectivity (FC) and insomnia symptoms in adolescents with MDD using a seed-based FC method. Methods: In the current study, we recruited sixty-eight first-episode drug-naïve adolescents with MDD and classified them into high insomnia (MDD-HI) and low insomnia (MDD-LI) groups according to the sleep disturbance subscale of the Hamilton Depression Rating Scale (HAMD-S). Forty-three age/gender-matched healthy controls (HCs) were also recruited. SCN FC maps were generally for all subjects and compared among three groups using one-way ANOVA with age, gender and adjusted HAMD score as covariates. We used partial correlations to explore associations between altered FC and clinical symptoms, including sleep quality scores. Results: Adolescents with MDD showed worse sleep quality, which positively correlated with the severity of depression. Compared to MDD-LI and HCs, MDD-HI adolescents demonstrated significantly decreased FC between the right SCN and bilateral precuneus, and there was no significant difference between the MDD-LI and HC groups. The HAMD-S scores were negatively correlated with bilateral SCN-precuneus connectivity, and the retardation factor score of HAMD was negatively correlated with right SCN-precuneus connectivity. Conclusion: The altered FC between the SCN and precuneus may underline the neural mechanism of sleep-related symptoms in depressive adolescents and provide potential targets for personalized treatment strategies.

Multivariate associations between behavioural dimensions and white matter across children and adolescents with and without attention-deficit/hyperactivity disorder.

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder. Integrity of white matter microstructure plays a key role in the neural mechanism of ADHD presentations. However, the relationships between specific behavioural dimensions and white matter microstructure are less well known. This study aimed to identify associations between white matter and a broad set of clinical features across children and adolescent with and without ADHD using a data-driven multivariate approach. METHOD: We recruited a total of 130 children (62 controls and 68 ADHD) and employed regularized generalized canonical correlation analysis to characterize the associations between white matter and a comprehensive set of clinical measures covering three domains, including symptom, cognition and behaviour. We further applied linear discriminant analysis to integrate these associations to explore potential developmental effects. RESULTS: We delineated two brain-behaviour dimensional associations in each domain resulting a total of six multivariate patterns of white matter microstructural alterations linked to hyperactivity-impulsivity and mild affected; executive functions and working memory; externalizing behaviour and social withdrawal, respectively. Apart from executive function and externalizing behaviour sharing similar white matter patterns, all other dimensions linked to a specific pattern of white matter microstructural alterations. The multivariate dimensional association scores showed an overall increase and normalization with age in ADHD group while remained stable in controls. CONCLUSIONS: We found multivariate neurobehavioral associations exist across ADHD and controls, which suggested that multiple white matter patterns underlie ADHD heterogeneity and provided neural bases for more precise diagnosis and individualized treatment.

Aberrant intrinsic hippocampal and orbitofrontal connectivity in drug-naive adolescent patients with major depressive disorder.

Alterations in resting-state functional connectivity (rsFC) of hippocampus and orbitofrontal cortex (OFC) have been highly implicated in major depressive disorder (MDD) and the researches have penetrated to the subregional level. However, relatively little is known about the intrinsic connectivity patterns of these two regions in adolescent MDD (aMDD), especially that of their functional subregions. Therefore, in the current study, we recruited 68 first-episode drug-naive aMDD patients and 43 matched typically developing controls (TDC) to characterize the alterations of whole-brain rsFC patterns in hippocampus and OFC at both regional and subregional levels in aMDD. The definition of specific functional subregions in hippocampus and OFC were based on the prior functional clustering-analysis results. Furthermore, the relationship between rsFC alterations and clinical features was also explored. Compared to TDC group, aMDD patients showed decreased connectivity of the left whole hippocampus with bilateral OFC and right inferior temporal gyrus at the regional level and increased connectivity between one of the right hippocampal subregions and right posterior insula at the subregional level. Reduced connectivity of OFC was only found in the subregion of left OFC with left anterior insula extending to lenticula in aMDD patients relative to TDC group. Our study identifies that the aberrant hippocampal and orbitofrontal rsFC was predominantly located in the insular cortex and could be summarized as an altered hippo-orbitofrontal-insular circuit in aMDD, which may be the unique features of brain network dysfunction in depression at this particular age stage. Moreover, we observed the distinct rsFC alterations in adolescent depression at the subregional level, especially the medial and lateral OFC.

Disorganized functional architecture of amygdala subregional networks in obsessive-compulsive disorder.

A precise understanding of amygdala-centered subtle networks may help refine neurocircuitry models of obsessive-compulsive disorder (OCD). We applied connectivity-based parcellation methodology to segment the amygdala based on resting-state fMRI data of 92 medication-free OCD patients without comorbidity and 90 matched healthy controls (HC). The amygdala was parcellated into two subregions corresponding to basolateral amygdala (BLA) and centromedial amygdala (CMA). Amygdala subregional functional connectivity (FC) maps were generated and group differences were evaluated with diagnosis-by-subregion flexible factorial ANOVA. We found significant diagnosis × subregion FC interactions in insula, supplementary motor area (SMA), midcingulate cortex (MCC), superior temporal gyrus (STG) and postcentral gyrus (PCG). In HC, the BLA demonstrated stronger connectivity with above regions compared to CMA, whereas in OCD, the connectivity pattern reversed to stronger CMA connectivity comparing to BLA. Relative to HC, OCD patients exhibited hypoconnectivity between left BLA and left insula, and hyperconnectivity between right CMA and SMA, MCC, insula, STG, and PCG. Moreover, OCD patients showed reduced volume of left BLA and right CMA compared to HC. Our findings characterized disorganized functional architecture of amygdala subregional networks in accordance with structural defects, providing direct evidence regarding the specific role of amygdala subregions in the neurocircuitry models of OCD.

The Effect of Nighttime Snacking on Cognitive Function in Older Adults: Evidence from Observational and Experimental Studies.

Evidence shows that supplementary snacking could provide older adults with nutrients that cannot be obtained through three meals a day. However, whether and how supplementary snacking, especially nighttime snacking, affects older adults' cognitive function remain unclear. The present study examined the effect of nighttime snacking on cognitive function for older adults. In study 1, we investigated the association between nighttime snacking and cognitive function based on data from 2618 community-dwelling older adults from the China health and nutrition survey (CHNS). In study 2, we conducted an experiment (n = 50) to explore how nighttime acute energy intake influences older adults' performance on cognitive tasks (immediate recall, short-term delayed recall, and long-term delayed recall). Both the observational and experimental studies suggested that nighttime snacking facilitated older adults' cognitive abilities, such as memory and mathematical ability, as indicated by subjective measures (study 1) and objective measures (studies 1 and 2). Moreover, this beneficial effect was moderated by cognitive load. These findings bridge the gap in the literature on the relationships between older adults' nighttime snacking and cognitive function, providing insight into how to improve older adults' dietary behaviors and cognitive function.

Abnormal resting-state functional connectivity in patients with obsessive-compulsive disorder: A systematic review and meta-analysis.

Obsessive-compulsive disorder (OCD) displays widespread disruption across brain regions revealed by resting-state functional connectivity (rsFC) with inconsistent results between studies. We performed a systematic review of 47 seed-based rsFC studies (1863 patients; 1795 healthy controls) to explore brain intrinsic connectivity alterations. Quantitative coordinate-based meta-analysis was conducted for seed regions in the striatum (putamen, caudate, nucleus accumbens [Nac]), thalamus, and anterior cingulate cortex (ACC) because there were an adequate number of studies. We found that OCD patients demonstrated (1) characteristic dysconnectivity between striatum and cortical networks (i.e., caudate hyperconnectivity with the fronto-limbic network and hypoconnectivity with frontoparietal network regions; Nac hypoconnectivity with fronto-limbic network regions), (2) hypoconnectivity between thalamus and striatum (putamen and caudate), and (3) dysconnectivity between the ACC and fronto-limbic network regions. Furthermore, there were negative correlations between particular connectivities and symptom severity and onset age. Our results characterize the traditional cortico-striato-thalamo-cortical circuit model of OCD pathophysiology through the cerebral intrinsic connectivity, and unified neurocircuitry and brain network models into one integrity to elaborate the neural mechanism of OCD.

Alterations in large-scale functional networks in adult posttraumatic stress disorder: A systematic review and meta-analysis of resting-state functional connectivity studies.

Posttraumatic stress disorder (PTSD) is associated with dysfunction in large-scale brain functional networks, as revealed by resting-state functional connectivity studies. However, it remains unclear which networks have been most consistently affected and, more importantly, what role disease and trauma may play in the disrupted functional networks. We performed a systematic review of studies exploring network alterations using seed-based functional connectivity analysis, comparing individuals with PTSD to controls in general as well as trauma-exposed or nonexposed controls specifically, and quantitative meta-analysis was conducted when the number of studies was appropriately high. We found that hypoconnectivity within the default-mode network (DMN) as well as between the affective network (AN) and DMN were specifically associated with traumatic experience. Additionally, hyperconnectivity between the AN and somatomotor network (SMN) and between the DMN and SMN were specifically related to PTSD. Our results emphasize the effect of trauma itself on alterations in intrinsic brain networks and highlight disease-associated network alterations, which may help us better understand the neural mechanisms of trauma and PTSD.

Efficacy and tolerability of repetitive transcranial magnetic stimulation for the treatment of obsessive-compulsive disorder in adults: a systematic review and network meta-analysis.

Repetitive transcranial magnetic stimulation (rTMS) has been widely used as an alternative treatment for obsessive-compulsive disorder (OCD). However, the most effective rTMS parameters, such as the targets and stimulation frequencies, remain controversial. Therefore, we aimed to compare and rank the efficacy and tolerability of different rTMS strategies for OCD treatment. We searched five electronic databases from the date of their inception to March 25, 2020. Pairwise meta-analyses and network meta-analyses were performed to synthesize data. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Twenty-two eligible randomized controlled trials (RCTs) were included. For efficacy, low-frequency (LF) rTMS over the dorsolateral prefrontal cortex (DLPFC; mean difference (MD) 6.34, 95% credible interval (CrI) 2.12-10.42) and supplementary motor area (MD 4.18, 95% CrI 0.83-7.62), and high-frequency rTMS over the DLPFC (MD 3.75, 95% CrI 1.04-6.81) were more effective than sham rTMS. Regarding tolerability, all rTMS treatment strategies were similar to the sham rTMS. The estimated ranking probabilities of treatments showed that LF-rTMS over the DLPFC might be the most effective intervention among all rTMS strategies. However, the quality of evidence regarding efficacy was evaluated as very low. Current evidence suggested a marginal advantage for LF-rTMS over the DLPFC on OCD treatment. High-quality RCTs with low selection and performance bias are needed to further verify the efficacy of specific rTMS strategies for the OCD treatment.

Family Conflict Associated With Intrinsic Hippocampal-OFC Connectivity in Adolescent Depressive Disorder.

BACKGROUND: Family environment and life events have long been suggested to be associated with adolescent depression. The hippocampus plays a crucial role in the neural mechanism of major depressive disorder (MDD) through memory during stressful events. However, few studies have explored the exact neural mechanisms underlying these associations. Thus, the current study aimed to explore alterations in hippocampal functional connectivity (FC) in adolescent MDD based on resting-state functional magnetic resonance imaging and further investigate the relationship between hippocampal FC, environmental factors, and clinical symptom severity. METHODS: Hippocampal FC was calculated using the seed-based approach with the bilateral hippocampus as the seed for 111 adolescents with and without MDD; comparisons were made between participants with MDD and controls. We applied the Chinese version of the Family Environment Scale (FES-CV) and Adolescents Self-Rating Life Events Checklist (ASLEC) to evaluate family environment and life stress. Their relationship with hippocampal FC alterations was also investigated. RESULTS: We found that compared to controls, adolescents with MDD showed decreased connectivity between the left hippocampus and bilateral orbital frontal cortex (OFC) and right inferior temporal gyrus. In addition, the hippocampal-OFC connectivity was negatively correlated with conflict scores of the FES-CV in the MDD group and mediated the association between family conflict and depressive and anxiety symptoms. CONCLUSION: Our findings are novel in the field and demonstrate how family conflict contributes to MDD symptomatology through hippocampal-OFC connectivity; these findings may provide potential targets for personalized treatment strategies.

Nitrogen-doped graphene quantum dots prepared by electrolysis of nitrogen-doped nanomesh graphene for the fluorometric determination of ferric ions.

Nitrogen-doped graphene quantum dots (N-GQDs) were synthesized by direct electrolysis of a carbon cloth electrode coated with nitrogen-doped nanomesh graphene (NG) in high yield (~ 25%). The N-GQDs emit intense blue fluorescence with a quantum yield (QY) of 10% ± 3%. Meanwhile, the N-GQDs are rich in hydroxyl, carboxyl, basic pyridinic nitrogen, and nitro groups, which are conducive to strengthen the interaction between N-GQDs and Fe3+ for highly sensitive determination of Fe3+ ions. Specifically, the determination for Fe3+ was conducted at different concentrations of N-GQD solution with a wide linear range of 10-1000 µM (150 µg·mL-1) and a low detection limit of 0.19 µM (10 µg·mL-1). Moreover, the fluorescence quenching mechanism illustrated that the functional groups generated by electrochemical oxidation enhanced the interaction of N-GQDs and Fe3+, and the narrow band gap (2.83 eV) of N-GQDs accomplished electron transfer from N-GQDs to Fe3+ easily. Graphical abstract A highly conductive carbon cloth electrode coated with nitrogen-doped nanomesh graphene (NG) was developed to prepared nitrogen-doped graphene quantum dots (N-GQDs) which was endowed with a wide linear range from 10 to 1000 µM (150 µg/mL) and a low detection limit of 0.19 µM (10 µg/mL) in the determination of Fe3+.

Interleukin-10 Protects Schwann Cells against Advanced Glycation End Products-Induced Apoptosis via NF-κB Suppression.

Demyelination resulting from Schwann cell injury is a main pathological feature of diabetic neuropathy, and a key contributor to this process may be inflammation due to advanced glycation end products (AGEs). Therefore, protection by anti-inflammation agents is anticipated. In this study, we showed that interleukin-10 (IL-10), an anti-inflammatory cytokine, inhibits apoptosis of Schwann cells induced by AGEs in vitro. We isolated and cultured Schwann cells from rat sciatic nerves. As detected by flow cytometry, apoptosis of Schwann cells markedly increased following incubation with AGEs for 48 h. However, pretreatment with IL-10 inhibited AGE-induced apoptosis. The effect of IL-10 on NF-κB, which is a very important regulator of inflammation, was also evaluated, and results showed high levels of phospho-NF-κB and nuclear localization of NF-κB in cells incubated with AGEs but low levels of phospho-NF-κB and cytoplasmic localization in the cells incubated with IL-10, indicating the activation of NF-κB by AGEs and inhibition of NF-κB by IL-10. Moreover, incubating Schwann cells with an NF-κB inhibitor (caffeic acid phenethyl ester) for 30 min before adding AGEs mimicked IL-10, lowering the amount of reactive oxygen species and activity of caspase-3 and also decreasing apoptosis in Schwann cells. These results indicate that IL-10 may protect Schwann cells against AGE-induced apoptosis by attenuating oxidative stress via the inhibition of activation of NF-κB.

Facile Synthesis of Well-Dispersed Ni2P on N-Doped Nanomesh Carbon Matrix as a High-Efficiency Electrocatalyst for Alkaline Hydrogen Evolution Reaction.

The development of non-noble metal hydrogen evolution catalysts that can replace Pt is crucial for efficient hydrogen production. Herein, we develop a type of well-dispersed Ni2P on N-doped nanomesh carbon (NC) electrocatalyst by a facile pyrolysis method, which shows excellent hydrogen evolution reaction (HER) catalytic performance. It is rather remarkable that the overpotential of Ni2P/NC prepared under optimal proportion is 108 mV at 10 mA·cm-2 current density in 1 M KOH solution with the tafel slope of 67.3 mV·dec-1, the catalytic activity has no significant attenuation after 1000 cycles of cyclic voltammetry (CV)method. The hydrogen evolution performance of the electrocatalytic is better than most similar catalysts in alkaline media. The unique mesh structure of the carbon component in the catalyst facilitates the exposure of the active site and reduces the impedance, which improves the efficiency of electron transport as well as ensuring the stability of the hydrogen evolution reaction. In addition, we prove that nitrogen doping and pore structure are also important factors affecting catalytic activity by control experiments. Our results show that N-doped nanomesh carbon, as an efficient support, combined with Ni2P nanoparticles is of great significance for the development of efficient hydrogen evolution electrodes.

The N-silylation of sulfoximines.

The copper-catalyzed N-silylation of sulfoximines was achieved in the presence of di-tert-butyl peroxide. Notably, alkyl, phenyl and alkoxyl silanes were all suitable reaction partners. Mechanistic studies revealed that N-silyl acetamide serves as the intermediate.