A study on the association between prefrontal functional connectivity and non-suicidal self-injury in adolescents with depression.

Objective: Among adolescents with depression, the occurrence of non-suicidal self-injury (NSSI) behavior is prevalent, constituting a high-risk factor for suicide. However, there has been limited research on the neuroimaging mechanisms underlying adolescent depression and NSSI behavior, and the potential association between the two remains unclear. Therefore, this study aims to investigate the alterations in functional connectivity (FC) of the regions in the prefrontal cortex with the whole brain, and elucidates the relationship between these alterations and NSSI behavior in adolescents with depression. Methods: A total of 68 participants were included in this study, including 35 adolescents with depression and 33 healthy controls. All participants underwent assessments using the 17-item Hamilton Depression Rating Scale (17-HAMD) and the Ottawa Self-Harm Inventory. In addition, functional magnetic resonance imaging (fMRI) data of the participants' brains were collected. Subsequently, the FCs of the regions in the prefrontal cortex with the whole brain was calculated. The FCs showing significant differences were then subjected to correlation analyses with 17-HAMD scores and NSSI behavior scores. Result: Compared to the healthy control group, the adolescent depression group exhibited decreased FCs in several regions, including the right frontal eye field, left dorsolateral prefrontal cortex, right orbitofrontal cortex, left insula and right anterior cingulate coetex. The 17-HAMD score was positively correlated with the frequency of NSSI behavior within 1 year (rs = 0.461, p = 0.005). The FC between the right anterior cingulate cortex and the right precuneus showed a negative correlation with the 17-HAMD scores (rs = -0.401, p = 0.023). Additionally, the FC between the right orbitofrontal cortex and the right insula, demonstrated a negative correlation with the frequency of NSSI behavior within 1 year (rs = -0.438, p = 0.012, respectively). Conclusion: Adolescents with depression showed decreased FCs of the prefrontal cortex with multiple brain regions, and some of these FCs were associated with the NSSI frequency within 1 year. This study provided neuroimaging evidence for the neurophysiological mechanisms underlying adolescent depression and its comorbidity with NSSI behavior.

Reinforcing 2D Single-Crystal Bi2O2CO3 with Additional Interlayer Carbonates by CO2-Assisted Solid-to-Solid Phase Transition.

A facile gaseous CO2 mediated solid-to-solid transformation principle is adopted to insert additional CO3 2- anions into the thin single-crystal nanosheets of Bi2O2CO3, which is built of periodic arrays of intrinsic CO3 2- anions and (Bi2O2)2+ layers. The additional CO3 2- anions create abundant defects. The Bi2O2CO3 nanosheets with rich interlayer CO3 2- exhibit superior electronic properties and charge transfer kinetics than the pristine single-crystal 2D Bi2O2CO3 and display enhanced catalytic activity in photocatalytic CO2 reduction reaction and the photocatalytic oxidative degradation of organic pollutants. This work thus illustrates interlayer engineering as a flexible means to build layered 2D materials with excellent properties.

Efficient Loading and Sustained Delivery of Methotrexate Using a Tip-Swellable Microneedle Array Patch for Psoriasis Treatment.

Methotrexate (MTX), a primary treatment for moderate to severe psoriasis, is limited in clinical use due to suboptimal results and severe side effects from subcutaneous (SC) injection and oral administration. Microneedles offer a promising alternative for direct MTX delivery to targeted skin lesions, but issues such as drug wastage, dosage inaccuracy, and limited drug residence time in the lesions remain. This study introduces a tip-swellable microneedle array patch (TSMAP) using photo-cross-linked methacrylated hyaluronic acid (MeHA) and biocompatible resin for effective MTX loading and sustained delivery. A two-cast micromolding with vacuum drying is employed to concentrate cross-linked MeHA in about 30% of the needle's height at the tip, thereby ensuring that only the TSMAP tip swells. Efficient MTX loading into TSMAP tips is achieved through a 30 s drug solution immersion and 10 min drying, potentially minimizing drug waste from incomplete skin insertion due to skin elasticity. The MTX-loaded TSMAP effectively penetrates both porcine and psoriasis-like mouse skin with its tips detaching from the resin substrate and embedding deeply into the skin tissue, thereby functioning as a drug release reservoir. TSMAP significantly prolongs drug retention in skin compared with SC injection and dissolvable microneedles. The in vivo study demonstrates that TSMAP-mediated MTX delivery substantially enhances therapeutic outcomes in alleviating psoriasis symptoms and downregulating psoriasis-associated cytokines, outperforming oral administration, SC injection, and dissolvable microneedles. Thus, TSMAP could offer an efficient and user-friendly alternative for drug administration in the treatment of various skin diseases.

Self-Healing Porous Microneedles Fabricated Via Cryogenic Micromoulding and Phase Separation for Efficient Loading and Sustained Delivery of Diverse Therapeutics.

Sustained-release drug delivery formulations are preferable for treating various diseases as they enhance and prolong efficacy, minimize adverse effects, and avoid frequent dosing. However, these formulations are associated with poor patient compliance, require trained personnel for administration, and involve harsh manufacturing conditions that compromise drug stability. Here, a self-healing biodegradable porous microneedle (PMN) patch is reported for sustained drug delivery. The PMN patch is fabricated by a cryogenic micromoulding followed by phase separation, leading to formation of interconnected pores on the surface and internals of MNs. The pores with self-healing feature enable the PMNs to load hydrophilic drugs with different molecular weights in a mild and efficient manner. The healed PMNs can easily penetrate into the skin under press and detach from the supporting substrate under shear, thereby acting as implantable drug reservoirs for achieving sustained release of drugs for at least 40 days. One-time administration of desired therapeutics using the sustained-release healed PMNs resulted in stronger and longer-lasting efficacy in mitigating psoriasis and eliciting immunity compared to conventional methods with multiple administrations. The self-healing PMN patch for self-administrated and long-acting drug delivery can eventually improve medication adherence in prophylactic and therapeutic protocols that typically require frequent dosages.

An Ultraswelling Microneedle Device for Facile and Efficient Drug Loading and Transdermal Delivery.

The advancement and extensive demand for transdermal therapies can benefit from a safe, and efficient and user-friendly transdermal technology with broad applicability in delivering various hydrophilic drugs. Here the design and proof of concept applications of an ultraswelling microneedle device that enables the facile and efficient loading and transdermal delivery of hydrophilic drugs with different molecular weights is reported. The device consists of a super-hydrophilic hydrogel microneedle array and a resin base substrate. Using a special micromolding technique that involves hydrated crosslinking and cryogenic-demolding, the microneedle part displays a rapid swelling ratio of ≈3800%, enabling the loading of drugs up to 500 kDa in molecular weight. The drug loading process using the device just involves incubating the microneedle part in a drug solution for 1 min, followed by 15 min of drying. The microneedles can easily penetrate the skin under press and detach from the base substrate under shear, thereby releasing the payload. Administration of desired therapeutic agents using the device outperformed conventional administration methods in mitigating psoriasis and eliciting immunity. This biocompatible device, capable of withstanding ethylene oxide sterilization, can enhance the efficacy and accessibility of transdermal therapies in research institutes, hospitals, and even home settings.

Spatial Heterogeneity and Strong Coupling of FeII /FeIII in an Individual Metal-Organic Framework Nanoparticle for Efficient CO2 Photoreduction.

The synthesis and characterization of an FeII /FeIII metal-organic framework (MOF) nanocrystal with spatial heterogeneity that arises from the non-uniform distribution of different valence states is disclosed. The FeII /FeIII -Ni Prussian blue analog (PBA) delivers superior photocatalytic performance in the selective CO2 reduction reaction thanks to the strong FeII /FeIII coupling, with CO yield up to 12.27 mmol g-1 h-1 and 90.6% selectivity under visible-light irradiation. Density functional theory calculation and experimental studies prove that the spatial heterogeneity of FeII /FeIII in the individual MOF nanocrystal not only directs and expedites the charge transfer within a catalyst particle but also creates the heterogeneity of catalytically-active Ni sites for efficient CO2 photoreduction. The current findings add to a growing literature of materials with compositional heterogeneity and provide a reference for future research.

Effect of Electroacupuncture Versus Cognitive Behavioral Therapy for Perimenopausal Insomnia: Protocol for a Noninferiority Randomized Controlled Trial.

BACKGROUND: Perimenopausal insomnia (PMI) has a high global incidence, which is common in middle-aged women and is more severe than nonmenopausal insomnia. Effective treatments with fewer side effects and more consistent repeatable results are needed. Acupuncture, a therapy based on traditional Chinese medicine, is safe and may be effective for PMI. It is widely accepted in Western countries, and evidence supports the use of acupuncture as a main or supplementary therapy. Cognitive behavioral therapy is also used to improve sleep quality. It has structured sessions and has been recommended as a first-line treatment for insomnia (cognitive behavioral therapy for insomnia [CBT-I]) by the American Association of Physicians. However, few randomized controlled trials have been conducted to compare the effectiveness of these 2 therapies. This study will be performed in perimenopausal women with insomnia to determine the efficacy of electroacupuncture (EA) versus CBT-I. OBJECTIVE: This study aimed to compare the preliminary effectiveness and safety of EA and CBT-I for PMI through a randomized controlled noninferiority study design. METHODS: This study is designed as an assessor-blinded, noninferiority, randomized controlled trial. A total of 160 eligible participants with PMI will be randomly divided into 2 groups to receive either EA or CBT-I. Participants in the EA group will receive electroacupuncture for 8 weeks. The intervention will be delivered 3 times weekly for a total of 12 sessions and 2 times weekly for the next 4 weeks. Meanwhile, participants in the control group will undergo CBT-I (once a week) for 8 weeks. Treatment will use 7 main acupoints (GV20, DU24, EX-HN3, EX-HN18, EX-CA1, RN6, and RN4) and an extra 4 acupoints based on syndrome differentiation. The primary outcome is the Insomnia Severity Index. The secondary outcome measures are the Pittsburgh Sleep Quality Index; Menopause-Specific Quality of Life; Menopause Rating Scale; Hamilton Depression Scale; Hamilton Anxiety Scale; hot flash score; and the level of estradiol, follicle-stimulating hormone, and luteinizing hormone in serum. Sleep architecture will be assessed using polysomnograms. RESULTS: Participants are currently being recruited. The first participant was enrolled in January 2023, marking the initiation of the recruitment phase. The recruitment process is expected to continue until January 2025, at which point data collection will commence. CONCLUSIONS: This trial represents a pioneering effort to investigate the efficacy and safety of EA and CBT-I as interventions for PMI. It is noteworthy that this study is conducted solely within a single center and involves Chinese participants, which is a limitation. Nonetheless, the findings of this study are expected to contribute valuable insights for clinicians engaged in the management of PMI. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2300070981; https://www.chictr.org.cn/showprojEN.html?proj=194561. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51767.

Co-delivery of dendritic cell vaccine and anti-PD-1 antibody with cryomicroneedles for combinational immunotherapy.

Combinational immunotherapy of dendritic cell (DC) vaccines and anti-programmed cell death protein 1 antibodies (aPD1) has been regarded as a promising strategy for cancer treatment because it not only induces tumor-specific T cell immune responses, but also prevents failure of T cell functions by the immune suppressive milieu of tumors. Microneedles have emerged as an innovative platform for efficient transdermal immunotherapies. However, co-delivery of DC vaccines and aPD1 via microneedles has not been studied since conventional microneedle platforms are unsuitable for fragile therapeutics like living cells and antibodies. This study employs our newly invented cryomicroneedles (cryoMNs) to co-deliver DC vaccines and aPD1 for the combinational immunotherapy. CryoMNs are fabricated by stepwise cryogenic micromoulding of cryogenic medium with pre-suspended DCs and aPD1, which are further integrated with a homemade handle for convenient application. The viability of DCs in cryoMNs remains above 85%. CryoMNs are mechanically strong enough to insert into porcine and mouse skin, successfully releasing DCs and aPD1 inside skin tissue after melting. Co-delivery of ovalbumin (OVA)-pulsed DCs (OVA-DCs) and aPD1 via cryoMNs induced higher antigen-specific cellular immune responses compared with the mono-delivery of OVA-DCs or aPD1. Finally, administration with cryoMNs co-encapsulated with OVA-DCs and aPD1 increases the infiltration of effector T cells in the tumor, resulting in stronger anti-tumor therapeutic efficacy in both prophylactic and therapeutic melanoma models compared with administration with cryoMNs loaded with OVA-DCs or aPD1. This study demonstrates the great potential of cryoMNs as a co-delivery system of therapeutic cells and biomacromolecules for combinational therapies.

A Rapidly Dissolvable Microneedle Patch with Tip-Accumulated Antigens for Efficient Transdermal Vaccination.

Dissolvable microneedles (DMNs) are an attractive alternative for vaccine delivery due to their user-friendly, skin-targeted, and minimally invasive features. However, vaccine waste and inaccurate dosage remain significant issues faced by DMNs, as the skin's elasticity makes it difficult to insert MNs completely. Here, a simple and reliable fabrication method are introduced based on two-casting micromolding with centrifugal drying to create a rapidly DMN patch made of hyaluronic acid. Ovalbumin (OVA), as the model antigens, is concentrated in the tip parts of the DMNs (60% of the needle height) to prevent antigen waste caused by skin elasticity. The time and temperature of the initial centrifugal drying significantly affect antigen distribution within the needle tips, with lower temperature facilitating antigen accumulation. The resulting DMN patch is able to penetrate the skin with enough mechanical strength and quickly release antigens into the skin tissue within 3 min. The in vivo study demonstrates that immunization of OVA with DMNs outperforms conventional vaccination routes, including subcutaneous and intramuscular injections, in eliciting both humoral and cellular immunity. This biocompatible DMN patch offers a promising and effective strategy for efficient and safe vaccination.

Localized Phase Transformation Triggering Lattice Matching of Metal Oxide and Carbonate Hydroxide for Efficient CO2 Photoreduction.

Orderly heterostructured catalysts, which integrate nanomaterials of complementary structures and dimensions into single-entity structures, have hold great promise for sustainability applications. In this work, it is showcased that air as green reagent can trigger in situ localized phase transformation and transform the metal carbonate hydroxide nanowires into ordered heterostructured catalyst. In single-crystal nanowire heterostructure, the in situ generated and nanosized Co3 O4 will be anchored in single-crystal Co6 (CO3 )2 (OH)8 nanowires spontaneously, triggered by the lattice matching between the (220) plane of Co3 O4 and the (001) plane of Co6 (CO3 )2 (OH)8 . The lattice matching allows intimate contact at heterointerface with well-defined orientation and strong interfacial coupling, and thus significantly expedites the transfer of photogenerated electrons from tiny Co3 O4 to catalytically active Co6 (CO3 )2 (OH)8 in single-crystal nanowire, which elevates the catalytic efficiency of metal carbonate catalyst in the CO2 reduction reaction (VCO = 19.46 mmol g-1 h-1 and VH2 = 11.53 mmol g-1 h-1 ). The present findings add to the growing body of knowledge on exploiting Earth-abundant metal-carbonate catalysts, and demonstrate the utility of localized phase transformation in constructing advanced catalysts for energy and environmental sustainability applications.

Mapping Neurophysiological Subtypes of Major Depressive Disorder Using Normative Models of the Functional Connectome.

BACKGROUND: Major depressive disorder (MDD) is a highly heterogeneous disorder that typically emerges in adolescence and can occur throughout adulthood. Studies aimed at quantitatively uncovering the heterogeneity of individual functional connectome abnormalities in MDD and identifying reproducibly distinct neurophysiological MDD subtypes across the lifespan, which could provide promising insights for precise diagnosis and treatment prediction, are still lacking. METHODS: Leveraging resting-state functional magnetic resonance imaging data from 1148 patients with MDD and 1079 healthy control participants (ages 11-93), we conducted the largest multisite analysis to date for neurophysiological MDD subtyping. First, we characterized typical lifespan trajectories of functional connectivity strength based on the normative model and quantitatively mapped the heterogeneous individual deviations among patients with MDD. Then, we identified neurobiological MDD subtypes using an unsupervised clustering algorithm and evaluated intersite reproducibility. Finally, we validated the subtype differences in baseline clinical variables and longitudinal treatment predictive capacity. RESULTS: Our findings indicated great intersubject heterogeneity in the spatial distribution and severity of functional connectome deviations among patients with MDD, which inspired the identification of 2 reproducible neurophysiological subtypes. Subtype 1 showed severe deviations, with positive deviations in the default mode, limbic, and subcortical areas and negative deviations in the sensorimotor and attention areas. Subtype 2 showed a moderate but converse deviation pattern. More importantly, subtype differences were observed in depressive item scores and the predictive ability of baseline deviations for antidepressant treatment outcomes. CONCLUSIONS: These findings shed light on our understanding of different neurobiological mechanisms underlying the clinical heterogeneity of MDD and are essential for developing personalized treatments for this disorder.

Abnormal dynamic functional connectivity of thalamic subregions in patients with first-episode, drug-naïve major depressive disorder.

Background: Recent studies have shown that major depressive disorder (MDD) is associated with altered intrinsic functional connectivity (FC) of the thalamus; however, investigations of these alterations at a finer time scale and the level of thalamic subregions are still lacking. Methods: We collected resting-state functional MRI data from 100 treatment-naïve, first-episode MDD patients and 99 age-, gender- and education-matched healthy controls (HCs). Seed-based whole-brain sliding window-based dFC analyses were performed for 16 thalamic subregions. Between-group differences in the mean and variance of dFC were determined using threshold-free cluster enhancement algorithm. For significant alterations, there relationships with clinical and neuropsychological variables were further examined via bivariate and multivariate correlation analyses. Results: Of all thalamic subregions, only the left sensory thalamus (Stha) showed altered variance of dFC in the patients characterized by increases with the left inferior parietal lobule, left superior frontal gyrus, left inferior temporal gyrus, and left precuneus, and decreases with multiple frontal, temporal, parietal, and subcortical regions. These alterations accounted for, to a great extent, clinical, and neuropsychological characteristics of the patients as revealed by the multivariate correlation analysis. In addition, the bivariate correlation analysis revealed a positive correlation between the variance of dFC between the left Stha and right inferior temporal gurus/fusiform and childhood trauma questionnaires scores (r = 0.562, P < 0.001). Conclusion: These findings suggest that the left Stha is the most vulnerable thalamic subregion to MDD, whose dFC alterations may serve as potential biomarkers for the diagnosis of the disease.

Resting-state functional connectivity of the raphe nuclei in major depressive Disorder: A Multi-site study.

Accumulating evidence showed that major depressive disorder (MDD) is characterized by a dysfunction of serotonin neurotransmission. Raphe nuclei are the sources of most serotonergic neurons that project throughout the brain. Incorporating measurements of activity within the raphe nuclei into the analysis of connectivity characteristics may contribute to understanding how neurotransmitter synthesized centers are involved in thepathogenesisof MDD. Here, we analyzed the resting-state functional magnetic resonance imaging (RS-fMRI) dataset from 1,148 MDD patients and 1,079 healthy individuals recruited across nine centers. A seed-based analysis with the dorsal raphe and median raphe nuclei was performed to explore the functional connectivity (FC) alterations. Compared to controls, for dorsal raphe, the significantly decreased FC linking with the right precuneus and median cingulate cortex were found; for median raphe, the increased FC linking with right superior cerebellum (lobules V/VI) was found in MDD patients. In further exploratory analyzes, MDD-related connectivity alterations in dorsal and median raphe nuclei in different clinical factors remained highly similar to the main findings, indicating these abnormal connectivities are a disease-related alteration. Our study highlights a functional dysconnection pattern of raphe nuclei in MDD with multi-site big data. These findings help improve our understanding of the pathophysiology of depression and provide evidence of the theoretical foundation for the development of novel pharmacotherapies.

Frequency-resolved connectome alterations in major depressive disorder: A multisite resting fMRI study.

BACKGROUND: Functional connectome studies have revealed widespread connectivity alterations in major depressive disorder (MDD). However, the low frequency bandpass filtering (0.01-0.08 Hz or 0.01-0.1 Hz) in most studies have impeded our understanding on whether and how these alterations are affected by frequency of interest. METHODS: Here, we performed frequency-resolved (0.01-0.06 Hz, 0.06-0.16 Hz and 0.16-0.24 Hz) connectome analyses using a large-sample resting-state functional MRI dataset of 1002 MDD patients and 924 healthy controls from seven independent centers. RESULTS: We reported significant frequency-dependent connectome alterations in MDD in left inferior parietal, inferior temporal, precentral, and fusiform cortices and bilateral precuneus. These frequency-dependent connectome alterations are mainly derived by abnormalities of medium- and long-distance connections and are brain network-dependent. Moreover, the connectome alteration of left precuneus in high frequency band (0.16-0.24 Hz) is significantly associated with illness duration. LIMITATIONS: Multisite harmonization model only removed linear site effects. Neurobiological underpinning of alterations in higher frequency (0.16-0.24 Hz) should be further examined by combining fMRI data with respiration, heartbeat and blood flow recordings in future studies. CONCLUSIONS: These results highlight the frequency-dependency of connectome alterations in MDD and the benefit of examining connectome alteration in MDD under a wider frequency band.

Scalable Synthesis of Holey Deficient 2D Co/NiO Single-Crystal Nanomeshes via Topological Transformation for Efficient Photocatalytic CO2 Reduction.

Preparation of holey, single-crystal, 2D nanomaterials containing in-plane nanosized pores is very appealing for the environment and energy-related applications. Herein, an in situ topological transformation is showcased of 2D layered double hydroxides (LDHs) allows scalable synthesis of holey, single-crystal 2D transition metal oxides (TMOs) nanomesh of ultrathin thickness. As-synthesized 2D Co/NiO-2 nanomesh delivers superior photocatalytic CO2 -syngas conversion efficiency (i.e., VCO of 32460 µmol h-1 g-1 CO and V H 2 ${V_{{{\rm{H}}_2}}}$ of 17840 µmol h-1 g-1 H2 ), with VCO about 7.08 and 2.53 times that of NiO and 2D Co/NiO-1 nanomesh containing larger pore size, respectively. As revealed in high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM), the high performance of Co/NiO-2 nanomesh primarily originates from the edge sites of nanopores, which carry more defect structures (e.g., atomic steps or vacancies) than basal plane for CO2 adsorption, and from its single-crystal structure adept at charge transport. Theoretical calculation shows the topological transformation from 2D hydroxide to holey 2D oxide can be achieved, probably since the trace Co dopant induces a lattice distortion and thus a sharp decrease of the dehydration energy of hydroxide precursor. The findings can advance the design of intriguing holey 2D materials with well-defined geometric and electronic properties.

Connectome gradient dysfunction in major depression and its association with gene expression profiles and treatment outcomes.

Patients with major depressive disorder (MDD) exhibit concurrent deficits in both sensory and higher-order cognitive processing. Connectome studies have suggested a principal primary-to-transmodal gradient in functional brain networks, supporting the spectrum from sensation to cognition. However, whether this gradient structure is disrupted in patients with MDD and how this disruption associates with gene expression profiles and treatment outcome remain unknown. Using a large cohort of resting-state fMRI data from 2227 participants (1148 MDD patients and 1079 healthy controls) recruited at nine sites, we investigated MDD-related alterations in the principal connectome gradient. We further used Neurosynth, postmortem gene expression, and an 8-week antidepressant treatment (20 MDD patients) data to assess the meta-analytic cognitive functions, transcriptional profiles, and treatment outcomes related to MDD gradient alterations, respectively. Relative to the controls, MDD patients exhibited global topographic alterations in the principal primary-to-transmodal gradient, including reduced explanation ratio, gradient range, and gradient variation (Cohen's d = 0.16-0.21), and focal alterations mainly in the primary and transmodal systems (d = 0.18-0.25). These gradient alterations were significantly correlated with meta-analytic terms involving sensory processing and higher-order cognition. The transcriptional profiles explained 53.9% variance of the altered gradient pattern, with the most correlated genes enriched in transsynaptic signaling and calcium ion binding. The baseline gradient maps of patients significantly predicted symptomatic improvement after treatment. These results highlight the connectome gradient dysfunction in MDD and its linkage with gene expression profiles and clinical management, providing insight into the neurobiological underpinnings and potential biomarkers for treatment evaluation in this disorder.

Subregion-specific, modality-dependent and timescale-sensitive hippocampal connectivity alterations in patients with first-episode, drug-naïve major depression disorder.

BACKGROUND: Despite accumulating evidence for the hippocampus as a key dysfunctional node in major depressive disorder (MDD), previous findings are controversial possibly due to heterogeneous and small clinical samples, complicated hippocampal structure, and different imaging modalities and analytical methods. METHODS: We collected structural and resting-state functional MRI data from 100 first-episode, drug-naïve MDD patients and 99 healthy controls. A subset of the participants (34 patients and 33 controls) also completed a battery of neuropsychological tests and childhood trauma questionnaires. Seed-based morphological and functional (static and dynamic) connectivity were calculated for ten hippocampal subregions, followed by analyses of dynamic functional connectivity states (k-means clustering), connectivity cross-modality relationships (cosine similarity), and connectivity associations with clinical and neuropsychological variables (Spearman correlation). RESULTS: Between-group comparisons revealed abnormal hippocampal connectivity in the patients that depended on 1) hippocampal subdivisions: the cornu ammonis (CA) was the most seriously affected subregion, in particular the right CA1 for functional connectivity alterations; 2) imaging modality: morphological connectivity revealed seldom and sporadic alterations with different lobes, while functional connectivity identified numerous and convergent alterations with prefrontal regions; and 3) time scale: dynamic functional connectivity was more sensitive than static functional connectivity, in particular in revealing alterations between the right CA1 and contralateral prefrontal cortex. Among the 34 patients, functional connectivity alterations of the CA1 were related to the history of childhood trauma in the patients. LIMITATIONS: Only a subset of the patients completed the neuropsychological tests, which may cause underestimation of cognitive relevance of hippocampal connectivity alterations. CONCLUSIONS: Disrupted hippocampal CA1 functional connectivity plays key roles in the pathophysiology of MDD and may act as a potential diagnostic biomarker for the disease.

A Chain Mediation Model of Perceived Stress, Neuroticism, and Psychological Inflexibility on Depressive Symptoms of Chinese New Fathers.

There is a growing concern about mental health issues in new fathers, such as postpartum depression (PPD). Factors associated with PPD in men include personality traits and perceived stress. This study examined a set of hypothesized paths using perceived stress, neuroticism, and psychological inflexibility to predict depressive symptoms. A total of 189 participants took part. The mean age of these first-time fathers was 36.12 years (SD = 2.39). Perceived stress, neuroticism, and psychological inflexibility positively predicted new fathers' depressive symptoms (B = 0.13, 0.37, and 0.31, respectively). These predictors explained 48% (R2 = 0.48) of the variance in the measured outcome of depressive symptoms in these new Chinese fathers. The total standardized direct effects of the three variables on depressive symptoms were 0.47 (95% CI [0.38, 0.53]). In conclusion, this study provides novel information about the chain mediating role played by neuroticism and psychological inflexibility in the relationship between perceived stress and PPD. Perceived stress significantly predicted neuroticism and psychological inflexibility, which in turn significantly predicted depressive symptoms in new Chinese fathers. The relationship between perceived stress and depressive symptoms was also mediated by each of psychological inflexibility or neuroticism alone.

Abnormal Functional Connectivity of Posterior Cingulate Cortex Correlates With Phonemic Verbal Fluency Deficits in Major Depressive Disorder.

Background: Major depressive disorder (MDD) patients face an increased risk of developing cognitive impairments. One of the prominent cognitive impairments in MDD patients is verbal fluency deficit. Nonetheless, it is not clear which vulnerable brain region in MDD is interactively linked to verbal fluency deficit. It is important to gain an improved understanding for verbal fluency deficit in MDD. Methods: Thirty-four MDD patients and 34 normal controls (NCs) completed resting-state fMRI (rs-fMRI) scan and a set of verbal fluency tests (semantic VFT and phonemic VFT). Fourteen brain regions from five brain networks/systems (central executive network, default mode network, salience network, limbic system, cerebellum) based on their vital role in MDD neuropathology were selected as seeds for functional connectivity (FC) analyses with the voxels in the whole brain. Finally, correlations between the z-score of the FCs from clusters showing significant between-group difference and z-score of the VFTs were calculated using Pearson correlation analyses. Results: Increased FCs in MDD patients vs. NCs were identified between the bilateral posterior cingulate cortex (PCC) and the right inferior frontal gyrus (triangular part), in which the increased FC between the right PCC and the right inferior frontal gyrus (triangular part) was positively correlated with the z score of phonemic VFT in the MDD patients. Moreover, decreased FCs were identified between the right hippocampal gyrus and PCC, as well as left cerebellum Crus II and right parahippocampal gyrus in MDD patients vs. NCs. Conclusions: The MDD patients have altered FCs among key brain regions in the default mode network, the central executive network, the limbic system, and the cerebellum. The increased FC between the right PCC and the right inferior frontal gyrus (triangular part) may be useful to better characterize pathophysiology of MDD and functional correlates of the phonemic verbal fluency deficit in MDD.

Multiscale neural modeling of resting-state fMRI reveals executive-limbic malfunction as a core mechanism in major depressive disorder.

Major depressive disorder (MDD) represents a grand challenge to human health and society, but the underlying pathophysiological mechanisms remain elusive. Previous neuroimaging studies have suggested that MDD is associated with abnormal interactions and dynamics in two major neural systems including the default mode - salience (DMN-SAL) network and the executive - limbic (EXE-LIM) network, but it is not clear which network plays a central role and which network plays a subordinate role in MDD pathophysiology. To address this question, we refined a newly developed Multiscale Neural Model Inversion (MNMI) framework and applied it to test whether MDD is more affected by impaired circuit interactions in the DMN-SAL network or the EXE-LIM network. The model estimates the directed connection strengths between different neural populations both within and between brain regions based on resting-state fMRI data collected from normal healthy subjects and patients with MDD. Results show that MDD is primarily characterized by abnormal circuit interactions in the EXE-LIM network rather than the DMN-SAL network. Specifically, we observe reduced frontoparietal effective connectivity that potentially contributes to hypoactivity in the dorsolateral prefrontal cortex (dlPFC), and decreased intrinsic inhibition combined with increased excitation from the superior parietal cortex (SPC) that potentially lead to amygdala hyperactivity, together resulting in activation imbalance in the PFC-amygdala circuit that pervades in MDD. Moreover, the model reveals reduced PFC-to-hippocampus excitation but decreased SPC-to-thalamus inhibition in MDD population that potentially lead to hypoactivity in the hippocampus and hyperactivity in the thalamus, consistent with previous experimental data. Overall, our findings provide strong support for the long-standing limbic-cortical dysregulation model in major depression but also offer novel insights into the multiscale pathophysiology of this debilitating disease.