Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys.

Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT. Moreover, blood transcriptome profiling revealed that mutant monkeys resembled RTT patients in immune gene dysregulation. Taken together, the stark similarity in phenotype and/or endophenotype between monkeys and patients suggested that gene-edited RTT founder monkeys would be of value for disease mechanistic studies as well as development of potential therapeutic interventions for RTT.

Co-representation of Functional Brain Networks Is Shaped by Cortical Myeloarchitecture and Reveals Individual Behavioral Ability.

Large-scale functional networks are spatially distributed in the human brain. Despite recent progress in differentiating their functional roles, how the brain navigates the spatial coordination among them and the biological relevance of this coordination is still not fully understood. Capitalizing on canonical individualized networks derived from functional MRI data, we proposed a new concept, that is, co-representation of functional brain networks, to delineate the spatial coordination among them. To further quantify the co-representation pattern, we defined two indexes, that is, the co-representation specificity (CoRS) and intensity (CoRI), for separately measuring the extent of specific and average expression of functional networks at each brain location by using the data from both sexes. We found that the identified pattern of co-representation was anchored by cortical regions with three types of cytoarchitectural classes along a sensory-fugal axis, including, at the first end, primary (idiotypic) regions showing high CoRS, at the second end, heteromodal regions showing low CoRS and high CoRI, at the third end, paralimbic regions showing low CoRI. Importantly, we demonstrated the critical role of myeloarchitecture in sculpting the spatial distribution of co-representation by assessing the association with the myelin-related neuroanatomical and transcriptomic profiles. Furthermore, the significance of manifesting the co-representation was revealed in its prediction of individual behavioral ability. Our findings indicated that the spatial coordination among functional networks was built upon an anatomically configured blueprint to facilitate neural information processing, while advancing our understanding of the topographical organization of the brain by emphasizing the assembly of functional networks.

Structural and functional abnormalities in first-episode drug-naïve pediatric idiopathic generalized epilepsy.

The aim of this study was to investigate brain structure and corresponding static and dynamic functional connectivity (sFC & dFC) abnormalities in untreated, first-episode pediatric idiopathic generalized epilepsy (IGE), with the goal of better understanding the underlying pathological mechanisms of IGE. Thirty-one children with IGE and 31 age-matched healthy controls (HC) were recruited. Structural magnetic resonance imaging (sMRI) data were acquired, and voxel-based morphometry (VBM) analysis were performed to reveal abnormal gray matter volume (GMV). Moreover, sFC and dFC analyses were conducted using the brain areas exhibiting abnormal GMV as seed regions to explore abnormal functional couplings. Compared to HC, the IGE group exhibited increased GMV in left middle cingulate cortex (MCC) and right parahippocampus (ParaHipp). In addition, the analyses of dFC and sFC with MCC and ParaHipp as seeds revealed more extensive functional connectivity (FC) changes in dFC. Notably, the structurally and functionally abnormal brain areas were primarily localized in the default mode network (DMN). However, our study did not find any significant associations between these altered neuroimaging measurements and clinical outcomes. This study uncovered microstructural changes as well as corresponding sFC and dFC changes in patients with new-onset, untreated pediatric IGE. The affected brain regions were primarily located within the DMN, highlighting the DMN's crucial role in the development of pediatric IGE.

Mapping individual structural covariance network in development brain with dynamic time warping.

A conspicuous property of brain development or maturity is coupled with coordinated or synchronized brain structural co-variation. However, there is still a lack of effective approach to map individual structural covariance network. Here, we developed a novel individual structural covariance network method using dynamic time warping algorithm and applied it to delineate developmental trajectories of topological organizations of structural covariance network from childhood to early adulthood with a large sample of 655 individuals from Human Connectome Project-Development dataset. We found that the individual structural covariance network exhibited small-worldness property and the network global topological characteristics including small-worldness, global efficiency, local efficiency, and modularity linearly increase with age while the shortest path length linearly decreases with age. The nodal topological properties including betweenness and degree increased with age in language and emotion regulation related brain areas, while it decreased with age mainly in visual cortex, sensorimotor area, and hippocampus. Moreover, the topological attributes of structural covariance network as features could predict the age of each individual. Taken together, our results demonstrate that dynamic time warping can effectively map individual structural covariance network to uncover the developmental trajectories of network topology, which may facilitate future investigations to establish the links of structural co-variations with respect to cognition and disease vulnerability.

Molecular basis underlying default mode network functional abnormalities in postpartum depression with and without anxiety.

Although Postpartum depression (PPD) and PPD with anxiety (PPD-A) have been well characterized as functional disruptions within or between multiple brain systems, however, how to quantitatively delineate brain functional system irregularity and the molecular basis of functional abnormalities in PPD and PPD-A remains unclear. Here, brain sample entropy (SampEn), resting-state functional connectivity (RSFC), transcriptomic and neurotransmitter density data were used to investigate brain functional system irregularity, functional connectivity abnormalities and associated molecular basis for PPD and PPD-A. PPD-A exhibited higher SampEn in medial prefrontal cortex (MPFC) and posterior cingulate cortex (PPC) than healthy postnatal women (HPW) and PPD while PPD showed lower SampEn in PPC compared to HPW and PPD-A. The functional connectivity analysis with MPFC and PPC as seed areas revealed decreased functional couplings between PCC and paracentral lobule and between MPFC and angular gyrus in PPD compared to both PPD-A and HPW. Moreover, abnormal SampEn and functional connectivity were associated with estrogenic level and clinical symptoms load. Importantly, spatial association analyses between functional changes and transcriptome and neurotransmitter density maps revealed that these functional changes were primarily associated with synaptic signaling, neuron projection, neurotransmitter level regulation, amino acid metabolism, cyclic adenosine monophosphate (cAMP) signaling pathways, and neurotransmitters of 5-hydroxytryptamine (5-HT), norepinephrine, glutamate, dopamine and so on. These results reveal abnormal brain entropy and functional connectivities primarily in default mode network (DMN) and link these changes to transcriptome and neurotransmitters to establish the molecular basis for PPD and PPD-A for the first time. Our findings highlight the important role of DMN in neuropathology of PPD and PPD-A.

Identifying autism spectrum disorder using edge-centric functional connectivity.

Brain network analysis is an effective method to seek abnormalities in functional interactions for brain disorders such as autism spectrum disorder (ASD). Traditional studies of brain networks focus on the node-centric functional connectivity (nFC), ignoring interactions of edges to miss much information that facilitates diagnostic decisions. In this study, we present a protocol based on an edge-centric functional connectivity (eFC) approach, which significantly improves classification performance by utilizing the co-fluctuations information between the edges of brain regions compared with nFC to build the classification mode for ASD using the multi-site dataset Autism Brain Imaging Data Exchange I (ABIDE I). Our model results show that even using the traditional machine-learning classifier support vector machine (SVM) on the challenging ABIDE I dataset, relatively high performance is achieved: 96.41% of accuracy, 98.30% of sensitivity, and 94.25% of specificity. These promising results suggest that the eFC can be used to build a reliable machine-learning framework to diagnose mental disorders such as ASD and promote identifications of stable and effective biomarkers. This study provides an essential complementary perspective for understanding the neural mechanisms of ASD and may facilitate future investigations on early diagnosis of neuropsychiatric disorders.

Structural and functional changes in drug-naïve benign childhood epilepsy with centrotemporal spikes and their associated gene expression profiles.

Benign epilepsy with centrotemporal spikes (BECTS) is a common pediatric epilepsy syndrome that has been widely reported to show abnormal brain structure and function. However, the genetic mechanisms underlying structural and functional changes remain largely unknown. Based on the structural and resting-state functional magnetic resonance imaging data of 22 drug-naïve children with BECTS and 33 healthy controls, we conducted voxel-based morphology (VBM) and fractional amplitude of low-frequency fluctuation (fALFF) analyses to compare cortical morphology and spontaneous brain activity between the 2 groups. In combination with the Allen Human Brain Atlas, transcriptome-neuroimaging spatial correlation analyses were applied to explore gene expression profiles associated with gray matter volume (GMV) and fALFF changes in BECTS. VBM analysis demonstrated significantly increased GMV in the right brainstem and right middle cingulate gyrus in BECTS. Moreover, children with BECTS exhibited significantly increased fALFF in left temporal pole, while decreased fALFF in right thalamus and left precuneus. These brain structural and functional alterations were closely related to behavioral and cognitive deficits, and the fALFF-linked gene expression profiles were enriched in voltage-gated ion channel and synaptic activity as well as neuron projection. Our findings suggest that brain morphological and functional abnormalities in children with BECTS involve complex polygenic genetic mechanisms.

Classification of major depressive disorder using an attention-guided unified deep convolutional neural network and individual structural covariance network.

Major depressive disorder (MDD) is the second leading cause of disability worldwide. Currently, the structural magnetic resonance imaging-based MDD diagnosis models mainly utilize local grayscale information or morphological characteristics in a single site with small samples. Emerging evidence has demonstrated that different brain structures in different circuits have distinct developmental timing, but mature coordinately within the same functional circuit. Thus, establishing an attention-guided unified classification framework with deep learning and individual structural covariance networks in a large multisite dataset could facilitate developing an accurate diagnosis strategy. Our results showed that attention-guided classification could improve the classification accuracy from primary 75.1% to ultimate 76.54%. Furthermore, the discriminative features of regional covariance connectivities and local structural characteristics were found to be mainly located in prefrontal cortex, insula, superior temporal cortex, and cingulate cortex, which have been widely reported to be closely associated with depression. Our study demonstrated that our attention-guided unified deep learning framework may be an effective tool for MDD diagnosis. The identified covariance connectivities and structural features may serve as biomarkers for MDD.

Molecular mechanisms underlying human spatial cognitive ability revealed with neurotransmitter and transcriptomic mapping.

Mental rotation, one of the cores of spatial cognitive abilities, is closely associated with spatial processing and general intelligence. Although the brain underpinnings of mental rotation have been reported, the cellular and molecular mechanisms remain unexplored. Here, we used magnetic resonance imaging, a whole-brain spatial distribution atlas of 19 neurotransmitter receptors, transcriptomic data from Allen Human Brain Atlas, and mental rotation performances of 356 healthy individuals to identify the genetic/molecular foundation of mental rotation. We found significant associations of mental rotation performance with gray matter volume and fractional amplitude of low-frequency fluctuations in primary visual cortex, fusiform gyrus, primary sensory-motor cortex, and default mode network. Gray matter volume and fractional amplitude of low-frequency fluctuations in these brain areas also exhibited significant sex differences. Importantly, spatial correlation analyses were conducted between the spatial patterns of gray matter volume or fractional amplitude of low-frequency fluctuations with mental rotation and the spatial distribution patterns of neurotransmitter receptors and transcriptomic data, and identified the related genes and neurotransmitter receptors associated with mental rotation. These identified genes are localized on the X chromosome and are mainly involved in trans-synaptic signaling, transmembrane transport, and hormone response. Our findings provide initial evidence for the neural and molecular mechanisms underlying spatial cognitive ability.

Neural signatures of default mode network in major depression disorder after electroconvulsive therapy.

Functional abnormalities of default mode network (DMN) have been well documented in major depressive disorder (MDD). However, the association of DMN functional reorganization with antidepressant treatment and gene expression is unclear. Moreover, whether the functional interactions of DMN could predict treatment efficacy is also unknown. Here, we investigated the link of treatment response with functional alterations of DMN and gene expression with a comparably large sample including 46 individuals with MDD before and after electroconvulsive therapy (ECT) and 46 age- and sex-matched healthy controls. Static and dynamic functional connectivity (dFC) analyses showed increased intrinsic/static but decreased dynamic functional couplings of inter- and intra-subsystems and between nodes of DMN. The changes of static functional connections of DMN were spatially correlated with brain gene expression profiles. Moreover, static and dFC of the DMN before treatment as features could predict depressive symptom improvement following ECT. Taken together, these results shed light on the underlying neural and genetic basis of antidepressant effect of ECT and the intrinsic functional connectivity of DMN have the potential to serve as prognostic biomarkers to guide accurate personalized treatment.

Volume of hippocampus-amygdala transition area predicts outcomes of electroconvulsive therapy in major depressive disorder: high accuracy validated in two independent cohorts.

BACKGROUND: Although many previous studies reported structural plasticity of the hippocampus and amygdala induced by electroconvulsive therapy (ECT) in major depressive disorder (MDD), yet the exact roles of both areas for antidepressant effects are still controversial. METHODS: In the current study, segmentation of amygdala and hippocampal sub-regions was used to investigate the longitudinal changes of volume, the relationship between volume and antidepressant effects, and prediction performances for ECT in MDD patients before and after ECT using two independent datasets. RESULTS: As a result, MDD patients showed selectively and consistently increased volume in the left lateral nucleus, right accessory basal nucleus, bilateral basal nucleus, bilateral corticoamygdaloid transition (CAT), bilateral paralaminar nucleus of the amygdala, and bilateral hippocampus-amygdala transition area (HATA) after ECT in both datasets, whereas marginally significant increase of volume in bilateral granule cell molecular layer of the head of dentate gyrus, the bilateral head of cornu ammonis (CA) 4, and left head of CA 3. Correlation analyses revealed that increased volume of left HATA was significantly associated with antidepressant effects after ECT. Moreover, volumes of HATA in the MDD patients before ECT could be served as potential biomarkers to predict ECT remission with the highest accuracy of 86.95% and 82.92% in two datasets (The predictive models were trained on Dataset 2 and the sensitivity, specificity and accuracy of Dataset 2 were obtained from leave-one-out-cross-validation. Thus, they were not independent and very likely to be inflated). CONCLUSIONS: These results not only suggested that ECT could selectively induce structural plasticity of the amygdala and hippocampal sub-regions associated with antidepressant effects of ECT in MDD patients, but also provided potential biomarkers (especially HATA) for effectively and timely interventions for ECT in clinical applications.

Abnormal dynamics of resting-state functional activity and couplings in postpartum depression with and without anxiety.

Postpartum depression (PPD) and PPD comorbid with anxiety (PPD-A) are highly prevalent and severe mental health problems in postnatal women. PPD and PPD-A share similar pathopsychological features, leading to ongoing debates regarding the diagnostic and neurobiological uniqueness. This paper aims to delineate common and disorder-specific neural underpinnings and potential treatment targets for PPD and PPD-A by characterizing functional dynamics with resting-state functional magnetic resonance imaging in 138 participants (45 first-episode, treatment-naïve PPD; 31 PDD-A patients; and 62 healthy postnatal women [HPW]). PPD-A group showed specifically increased dynamic amplitude of low-frequency fluctuation in the subgenual anterior cingulate cortex (sgACC) and increased dynamic functional connectivity (dFC) between the sgACC and superior temporal sulcus. PPD group exhibited specifically increased static FC (sFC) between the sgACC and ventral anterior insula. Common disrupted sFC between the sgACC and middle temporal gyrus was found in both PPD and PPD-A patients. Interestingly, dynamic changes in dFC between the sgACC and superior temporal gyrus could differentiate PPD, PPD-A, and HPW. Our study presents initial evidence on specifically abnormal functional dynamics of limbic, emotion regulation, and social cognition systems in patients with PDD and PPD-A, which may facilitate understanding neurophysiological mechanisms, diagnosis, and treatment for PPD and PPD-A.

Modulating Gamma Oscillations Promotes Brain Connectivity to Improve Cognitive Impairment.

Dementia causes a substantial global economic burden, but effective treatment is lacking. Recently, studies have revealed that gamma-band waves of electrical brain activity, particularly 40 Hz oscillations, are closely associated with high-order cognitive functions and can activate microglia to clear amyloid-ß deposition. Here, we found that compared with sham stimulation, applying 40-Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) over the bilateral angular gyrus in patients with probable Alzheimer's disease (AD; n = 37) resulted in up to 8 weeks of significantly improved cognitive function. Power spectral density analysis of the resting-state electroencephalography (EEG) demonstrated that 40-Hz rTMS modulated gamma-band oscillations in the left posterior temporoparietal region. Further testing with magnetic resonance imaging and TMS-EEG revealed the following: 40-Hz rTMS 1) prevented gray matter volume loss, 2) enhanced local functional integration within bilateral angular gyrus, as well as global functional integration in bilateral angular gyrus and the left middle frontal gyrus, 3) strengthened information flow from the left posterior temporoparietal region to the frontal areas and strengthened the dynamic connectivity between anterior and posterior brain regions. These findings demonstrate that modulating gamma-band oscillations effectively improves cognitive function in patients with probable AD by promoting local, long-range, and dynamic connectivity within the brain.

Prediction of childhood maltreatment and subtypes with personalized functional connectome of large-scale brain networks.

Childhood maltreatment (CM) has a long impact on physical and mental health of children. However, the neural underpinnings of CM are still unclear. In this study, we aimed to establish the associations between functional connectome of large-scale brain networks and influences of CM evaluated through Childhood Trauma Questionnaire (CTQ) at the individual level based on resting-state functional magnetic resonance imaging data of 215 adults. A novel individual functional mapping approach was employed to identify subject-specific functional networks and functional network connectivities (FNCs). A connectome-based predictive modeling (CPM) was used to estimate CM total and subscale scores using individual FNCs. The CPM established with FNCs can well predict CM total scores and subscale scores including emotion abuse, emotion neglect, physical abuse, physical neglect, and sexual abuse. These FNCs primarily involve default mode network, fronto-parietal network, visual network, limbic network, motor network, dorsal and ventral attention networks, and different networks have distinct contributions to predicting CM and subtypes. Moreover, we found that CM showed age and sex effects on individual functional connections. Taken together, the present findings revealed that different types of CM are associated with different atypical neural networks which provide new clues to understand the neurobiological consequences of childhood adversity.

Enduring effect of abuse: Childhood maltreatment links to altered theory of mind network among adults.

Childhood maltreatment (CM) confers a great risk of maladaptive development outcomes later in life, however, the neurobiological mechanism underlying this vulnerability is still unclear. The present study aimed to investigate the long-term consequences of CM on neural connectivity while controlling for psychiatric conditions, medication, and, substance abuse. A sample including adults with (n = 40) and without CM (n = 50) completed Childhood Trauma Questionnaire (CTQ), personality questionnaires, and resting-state functional magnetic resonance imaging scan were recruited for the current study. The whole-brain functional connectivity (FC) was evaluated using an unbiased, data-driven, multivariate pattern analysis method. Relative to controls, adults with CM suffered a higher level of temperament and impulsivity and showed decreased FC between the insula and superior temporal gyrus (STG) and between inferior parietal lobule (IPL) and middle frontal gyrus, STG, and dorsal anterior cingulate cortex (dACC), while increased FC between IPL and cuneus and superior frontal gyrus (SFG) regions. The FCs of IPL with dACC and SFG were correlated with the anxious and cyclothymic temperament and attentional impulsivity. Moreover, these FCs partially mediated the relationship between CM and attentional impulsivity. Our results suggest that CM has a significant effect on the modulation of FC within theory of mind (ToM) network even decades later in adulthood, and inform a new framework to account for how CM results in the development of impulsivity. The novel findings reveal the neurobiological consequences of CM and provide new clues to the prevention and intervention strategy to reduce the risk of the development of psychopathology.

White Matter Structural and Network Topological Changes Underlying the Behavioral Phenotype of MECP2 Mutant Monkeys.

To explore the brain structural basis underlying the behavioral abnormalities associated with Rett syndrome (RTT), we carried out detailed longitudinal noninvasive magnetic resonance imaging analyses of RTT monkey models created by gene-editing, from weaning, through adolescence, till sexual maturation. Here, we report abnormal developmental dynamics of brain white matter (WM) microstructures and network topological organizations via diffusion tensor imaging. Specifically, disrupted WM microstructural integrity was observed at 9 months, but recovered thereafter, whereas WM network topological properties showed persistent abnormal dynamics from 9 to 37 months. Changes in the WM microstructure and WM network topology were correlated well with RTT-associated behavioral abnormalities including sleep latency, environmental exploration, and conflict encounters. Deleterious and protracted early WM myelination process likely lead to abnormal synaptic pruning, resulting in poor functional segregations. Together, this study provides initial evidence for changes in WM microstructure and network topological organization, which may underlie the neuro-patho-etilogy of RTT.

Group-guided individual functional parcellation of the hippocampus and application to normal aging.

Aging is closely associated with cognitive decline affecting attention, memory and executive functions. The hippocampus is the core brain area for human memory, learning, and cognition processing. To delineate the individual functional patterns of hippocampus is pivotal to reveal the neural basis of aging. In this study, we developed a group-guided individual parcellation approach based on semisupervised affinity propagation clustering using the resting-state functional magnetic resonance imaging to identify individual functional subregions of hippocampus and to identify the functional patterns of each subregion during aging. A three-way group parcellation was yielded and was taken as prior information to guide individual parcellation of hippocampus into head, body, and tail in each subject. The superiority of individual parcellation of hippocampus is validated by higher intraregional functional similarities by compared to group-level parcellation results. The individual variations of hippocampus were associated with coactivation patterns of three typical functions of hippocampus. Moreover, the individual functional connectivities of hippocampus subregions with predefined target regions could better predict age than group-level functional connectivities. Our study provides a novel framework for individual brain functional parcellations, which may facilitate the future individual researches for brain cognitions and brain disorders and directing accurate neuromodulation.

Right inferior frontal gyrus: An integrative hub in tonal bilinguals.

Right hemispheric dominance in tonal bilingualism is still controversial. In this study, we investigated hemispheric dominance in 30 simultaneous Bai-Mandarin tonal bilinguals and 28 Mandarin monolinguals using multimodal neuroimaging. Resting-state functional connectivity (RSFC) analysis was first performed to reveal the changes of functional connections within the language-related network. Voxel-based morphology (VBM) and tract-based spatial statistics (TBSS) analyses were then used to identify bilinguals' alterations in gray matter volume (GMV) and fractional anisotropy (FA) of white matter, respectively. RSFC analyses revealed significantly increased functional connections of the right pars-orbital part of the inferior frontal gyrus (IFG) with right caudate, right pars-opercular part of IFG, and left inferior temporal gyrus in Bai-Mandarin bilinguals compared to monolinguals. VBM and TBSS analyses further identified significantly greater GMV in right pars-triangular IFG and increased FA in right superior longitudinal fasciculus (SLF) in bilinguals than in monolinguals. Taken together, these results demonstrate the integrative role of the right IFG in tonal language processing of bilinguals. Our findings suggest that the intrinsic language network in simultaneous tonal bilinguals differs from that of monolinguals in terms of both function and structure.

The baby schema effect in adolescence and its difference from that in adulthood.

The baby schema effect induced by particular features of baby faces acts as an innate releasing mechanism that evokes positive emotions and instinctual behavioral responses. Our prior research in adults has revealed that this effect initially found in infancy extends into child faces. Adolescence is an important period involving development in various aspects of cognition, including face perception. Here, we investigated whether the extended baby schema effect we previously found in adult observers develops earlier-in adolescence-and how different it appears in adolescents as compared with in adults. In the current study, 76 adolescents and 77 adults were asked to judge the likeability of 148 neutral faces of infants and children (0.08-6.5 years of age) on 7-point scales. Results showed that both adolescents and adults perceived the faces of both infants and children younger than 4.6 years as more likeable relative to those of older children, indicating that the baby schema effect previously found in adulthood also occurs in adolescence. However, adolescents rated lower than adults toward the infant and child faces across all face ages, suggesting that this effect might be under development in adolescence. Overall, our findings provide new evidence for the development of face perception in adolescence and demonstrate age-related changes in innate releasing mechanisms in our protective and caretaking responses toward infants and children.

Combined static and dynamic functional connectivity signatures differentiating bipolar depression from major depressive disorder.

OBJECTIVE: Bipolar disorder in the depressive phase (BDd) may be misdiagnosed as major depressive disorder (MDD), resulting in poor treatment outcomes. To identify biomarkers distinguishing BDd from MDD is of substantial clinical significance. This study aimed to characterize specific alterations in intrinsic functional connectivity (FC) patterns in BDd and MDD by combining whole-brain static and dynamic FC. METHODS: A total of 40 MDD and 38 BDd patients, and 50 age-, sex-, education-, and handedness-matched healthy controls (HCs) were included in this study. Static and dynamic FC strengths (FCSs) were analyzed using complete time-series correlations and sliding window correlations, respectively. One-way analysis of variance was performed to test group effects. The combined static and dynamic FCSs were then used to distinguish BDd from MDD and to predict clinical symptom severity. RESULTS: Compared with HCs, BDd patients showed lower static FCS in the medial orbitofrontal cortex and greater static FCS in the caudate, while MDD patients exhibited greater static FCS in the medial orbitofrontal cortex. BDd patients also demonstrated greater static and dynamic FCSs in the thalamus compared with both MDD patients and HCs, while MDD patients exhibited greater dynamic FCS in the precentral gyrus compared with both BDd patients and HCs. Combined static and dynamic FCSs yielded higher accuracy than either static or dynamic FCS analysis alone, and also predicted anhedonia severity in BDd patients and negative mood severity in MDD patients. CONCLUSION: Altered FC within frontal-striatal-thalamic circuits of BDd patients and within the default mode network/sensorimotor network of MDD patients accurately distinguishes between these disorders. These unique FC patterns may serve as biomarkers for differential diagnosis and provide clues to the pathogenesis of mood disorders.