Examining the role of dopamine in methylphenidate's effects on resting brain function.

The amplitude of low-frequency fluctuations (ALFF) and global functional connectivity density (gFCD) are fMRI (Functional MRI) metrics widely used to assess resting brain function. However, their differential sensitivity to stimulant-induced dopamine (DA) increases, including the rate of DA rise and the relationship between them, have not been investigated. Here we used, simultaneous PET-fMRI to examine the association between dynamic changes in striatal DA and brain activity as assessed by ALFF and gFCD, following placebo, intravenous (IV), or oral methylphenidate (MP) administration, using a within-subject double-blind placebo-controlled design. In putamen, MP significantly reduced D2/3 receptor availability and strongly reduced ALFF and increased gFCD in the brain for IV-MP (Cohen's d > 1.6) but less so for oral-MP (Cohen's d < 0.6). Enhanced gFCD was associated with both the level and the rate of striatal DA increases, whereas decreased ALFF was only associated with the level of DA increases. These findings suggest distinct representations of neurovascular activation with ALFF and gFCD by stimulant-induced DA increases with differential sensitivity to the rate and the level of DA increases. We also observed an inverse association between gFCD and ALFF that was markedly enhanced during IV-MP, which could reflect an increased contribution from MP's vasoactive properties.

Maximum Classifier Discrepancy Generative Adversarial Network for Jointly Harmonizing Scanner Effects and Improving Reproducibility of Downstream Tasks.

OBJECTIVE: Multi-site collaboration is essential for overcoming small-sample problems when exploring reproducible biomarkers in MRI studies. However, various scanner-specific factors dramatically reduce the cross-scanner replicability. Moreover, existing harmony methods mostly could not guarantee the improved performance of downstream tasks. METHODS: we proposed a new multi-scanner harmony framework, called 'maximum classifier discrepancy generative adversarial network', or MCD-GAN, for removing scanner effects in the original feature space while preserving substantial biological information for downstream tasks. Specifically, the adversarial generative network was utilized for persisting the structural layout of each sample, and the maximum classifier discrepancy module was introduced for regulating GAN generators by incorporating the downstream tasks. RESULTS: We compared the MCD-GAN with other state-of-the-art data harmony approaches (e.g., ComBat, CycleGAN) on simulated data and the Adolescent Brain Cognitive Development (ABCD) dataset. Results demonstrate that MCD-GAN outperformed other approaches in improving cross-scanner classification performance while preserving the anatomical layout of the original images. SIGNIFICANCE: To the best of our knowledge, the proposed MCD-GAN is the first generative model which incorporates downstream tasks while harmonizing, and is a promising solution for facilitating cross-site reproducibility in various tasks such as classification and regression.

A Brainwide Risk Score for Psychiatric Disorder Evaluated in a Large Adolescent Population Reveals Increased Divergence Among Higher-Risk Groups Relative to Control Participants.

BACKGROUND: Accurate psychiatric risk assessment requires biomarkers that are both stable and adaptable to development. Functional network connectivity (FNC), which steadily reconfigures over time, potentially contains abundant information to assess psychiatric risks. However, the absence of suitable analytical methodologies has constrained this area of investigation. METHODS: We investigated the brainwide risk score (BRS), a novel FNC-based metric that contrasts the relative distances of an individual's FNC to that of psychiatric disorders versus healthy control references. To generate group-level disorder and healthy control references, we utilized a large brain imaging dataset containing 5231 total individuals diagnosed with schizophrenia, autism spectrum disorder, major depressive disorder, and bipolar disorder and their corresponding healthy control individuals. The BRS metric was employed to assess the psychiatric risk in 2 new datasets: Adolescent Brain Cognitive Development (ABCD) Study (n = 8191) and Human Connectome Project Early Psychosis (n = 170). RESULTS: The BRS revealed a clear, reproducible gradient of FNC patterns from low to high risk for each psychiatric disorder in unaffected adolescents. We found that low-risk ABCD Study adolescent FNC patterns for each disorder were strongly present in over 25% of the ABCD Study participants and homogeneous, whereas high-risk patterns of each psychiatric disorder were strongly present in about 1% of ABCD Study participants and heterogeneous. The BRS also showed its effectiveness in predicting psychosis scores and distinguishing individuals with early psychosis from healthy control individuals. CONCLUSIONS: The BRS could be a new image-based tool for assessing psychiatric vulnerability over time and in unaffected individuals, and it could also serve as a potential biomarker, facilitating early screening and monitoring interventions.

Triple Interactions Between the Environment, Brain, and Behavior in Children: An ABCD Study.

BACKGROUND: Environmental exposures play a crucial role in shaping children's behavioral development. However, the mechanisms by which these exposures interact with brain functional connectivity and influence behavior remain unexplored. METHODS: We investigated the comprehensive environment-brain-behavior triple interactions through rigorous association, prediction, and mediation analyses, while adjusting for multiple confounders. Particularly, we examined the predictive power of brain functional network connectivity (FNC) and 41 environmental exposures for 23 behaviors related to cognitive ability and mental health in 7655 children selected from the Adolescent Brain Cognitive Development (ABCD) Study at both baseline and follow-up. RESULTS: FNC demonstrated more predictability for cognitive abilities than for mental health, with cross-validation from the UK Biobank study (N = 20,852), highlighting the importance of thalamus and hippocampus in longitudinal prediction, while FNC+environment demonstrated more predictive power than FNC in both cross-sectional and longitudinal prediction of all behaviors, especially for mental health (r = 0.32-0.63). We found that family and neighborhood exposures were common critical environmental influencers on cognitive ability and mental health, which can be mediated by FNC significantly. Healthy perinatal development was a unique protective factor for higher cognitive ability, whereas sleep problems, family conflicts, and adverse school environments specifically increased risk of poor mental health. CONCLUSIONS: This work revealed comprehensive environment-brain-behavior triple interactions based on the ABCD Study, identified cognitive control and default mode networks as the most predictive functional networks for a wide repertoire of behaviors, and underscored the long-lasting impact of critical environmental exposures on childhood development, in which sleep problems were the most prominent factors affecting mental health.

Disrupted brain state dynamics in opioid and alcohol use disorder: attenuation by nicotine use.

Substance use disorder (SUD) is a chronic relapsing disorder with long-lasting changes in brain intrinsic networks. While most research to date has focused on static functional connectivity, less is known about the effect of chronic drug use on dynamics of brain networks. Here we investigated brain state dynamics in individuals with opioid use (OUD) and alcohol use disorder (AUD) and assessed how concomitant nicotine use, which is frequent among individuals with OUD and AUD, affects brain dynamics. Resting-state functional magnetic resonance imaging data of 27 OUD, 107 AUD, and 137 healthy participants were included in the analyses. To identify recurrent brain states and their dynamics, we applied a data-driven clustering approach that determines brain states at a single time frame. We found that OUD and AUD non-smokers displayed similar changes in brain state dynamics including decreased fractional occupancy or dwell time in default mode network (DMN)-dominated brain states and increased appearance rate in visual network (VIS)-dominated brain states, which were also reflected in transition probabilities of related brain states. Interestingly, co-use of nicotine affected brain states in an opposite manner by lowering VIS-dominated and enhancing DMN-dominated brain states in both OUD and AUD participants. Our finding revealed a similar pattern of brain state dynamics in OUD and AUD participants that differed from controls, with an opposite effect for nicotine use suggesting distinct effects of various drugs on brain state dynamics. Different strategies for treating SUD may need to be implemented based on patterns of co-morbid drug use.

Multi-scale convolutional recurrent neural network for psychiatric disorder identification in resting-state EEG.

Background: Accurate classification based on affordable objective neuroimaging biomarkers are important steps toward designing individualized treatment. Methods: In this work, we investigated a deep learning classification model, multi-scale convolutional recurrent neural network (MCRNN), to explore psychiatric disorder-related biomarkers by leveraging the spatiotemporal information of resting-state EEG (rsEEG) using a multiple psychiatric disorder database containing 327 individuals diagnosed with schizophrenia, bipolar, major depressive disorders, and healthy controls. All subjects were mapped to a shared low-dimensional subspace for intuitively interpreting the inter-relationship and separation of psychiatric disorders. Results: Psychiatric disorders were identified using rsEEG with high accuracy ranged from 78.6 to 91.3% in patient vs. controls two-class classification, and 68.2% in four-class classification. The control-to-schizophrenia trajectory interpretated by the model was consistent with the disease severity in clinical observation. Conclusion: The MsRNN demonstrated a capability in extracting discriminative rsEEG biomarkers for psychiatric disorder classification, indicating its potential to facilitate our understanding of psychiatric disorders and monitoring interventions.

'Harmless' adversarial network harmonization approach for removing site effects and improving reproducibility in neuroimaging studies.

Multi-site collaboration, which gathers together samples from multiple sites, is a powerful way to overcome the small-sample problem in the neuroimaging field and has the potential to discover more robust and reproducible biomarkers. However, confounds among the datasets caused by various site-specific factors may dramatically reduce the cross-site reproducibility performance. To properly remove confounds while improving cross-site task performances, we propose a maximum classifier discrepancy generative adversarial network (MCD-GAN) that combines the advantages of generative models and maximum discrepancy theory. The mechanisms of MCD-GAN and how it harmonizes the dataset are visualized using simulated data. The performance of MCD-GAN was also compared with state-of-the-art methods (e.g., ComBat, cycle-GAN) within Adolescent Brain Cognitive Development (ABCD) dataset. Result demonstrates that the proposed MCD-GAN can effectively improve the cross-site gender classification performance by harmonizing site effects. Our proposed framework is also suitable for various classification/prediction tasks and is promising to facilitate the cross-site reproducibility of neuroimaging studies. Clinical Relevance- This work provides an efficient method for removing sites effects and improving reproducibility in large-cohort neuroimaging studies.

Mapping relationships among schizophrenia, bipolar and schizoaffective disorders: A deep classification and clustering framework using fMRI time series.

BACKGROUND: Psychiatric disorders are categorized using self-report and observational information rather than biological data. There is also considerable symptomatic overlap between different types of psychiatric disorders, which makes diagnostic categorization and multi-class classification challenging. METHODS: In this work, we propose a unified framework for supervised classification and unsupervised clustering of psychotic disorders using brain imaging data. A new multi-scale recurrent neural network (MsRNN) model was developed and applied to fMRI time courses (TCs) for multi-class classification. The high-level representations of the original TCs were then submitted to a tSNE clustering model for visualizing the group differences between disorders. A leave-one-feature-out approach was used for disorder-related biomarker identification. RESULTS: When studying fMRI from schizophrenia, psychotic bipolar disorder, schizoaffective disorder, and healthy individuals, the accuracy of a 4-class classification reached 46%, significantly above chance. The hippocampus, supplementary motor area and paracentral lobule were discovered as the most contributing regional TCs in the multi-class classification. Beyond this, visualization of the tSNE clustering suggested that the disease severity can be captured and schizoaffective disorder (SAD) may be separated into two subtypes. SAD cluster1 has significantly higher Positive And Negative Syndrome Scale (PANSS) scores than SAD cluster2 in PANSS negative2 (emotional withdrawal), general2 (anxiety), general3 (guilt feelings), general4 (tension). CONCLUSIONS: The proposed deep classification and clustering framework is not only able to identify psychiatric disorders with high accuracy, but also interpret the correlation between brain networks and specific psychiatric disorders, and reveal the relationship between them. This work provides a promising way to investigate a spectrum of similar disorders using neuroimaging-based measures.

A fast online questionnaire for screening mental illness symptoms during the COVID-19 pandemic.

The COVID-19 pandemic has caused massive effects on the situation of public mental health. A fast online questionnaire for screening and evaluating mental symptoms is urgent. In this work, we developed a new 19-item self-assessment Fast Screen Questionnaire for Mental Illness Symptoms (FSQ-MIS) to quickly identify mental illness symptoms. The FSQ-MIS was validated on a total of 3828 young adult mental disorder patients and 984 healthy controls. We applied principal component analysis (PCA), receiver operating characteristic (ROC) curve, and general log-linear analysis (GLA) to evaluate the construct and parallel validity. Results demonstrate that the proposed FSQ-MIS shows high test-retest reliability (0.852) and split-half reliability (0.844). Six factors obtained using PCA explained 54.3% of the variance and showed high correlations with other widely used scales. The ROC results (0.716-0.983) revealed high criterion validity of FSQ-MIS. GLA demonstrated the advantage of FSQ-MIS in predicting anxiety and depression prevalence in COVID-19, supporting the efficiency of FSQ-MIS as a tool for research and clinical practice.

An attention-based hybrid deep learning framework integrating brain connectivity and activity of resting-state functional MRI data.

Functional magnetic resonance imaging (fMRI) as a promising tool to investigate psychotic disorders can be decomposed into useful imaging features such as time courses (TCs) of independent components (ICs) and functional network connectivity (FNC) calculated by TC cross-correlation. TCs reflect the temporal dynamics of brain activity and the FNC characterizes temporal coherence across intrinsic brain networks. Both features have been used as input to deep learning approaches with decent results. However, few studies have tried to leverage their complementary information to learn optimal representations at multiple facets. Motivated by this, we proposed a Hybrid Deep Learning Framework integrating brain Connectivity and Activity (HDLFCA) together by combining convolutional recurrent neural network (C-RNN) and deep neural network (DNN), aiming to improve classification accuracy and interpretability simultaneously. Specifically, C-RNNAM was proposed to extract temporal dynamic dependencies with an attention module (AM) to automatically learn discriminative knowledge from TC nodes, while DNN was applied to identify the most group-discriminative FNC patterns with layer-wise relevance propagation (LRP). Then, both prediction outputs were concatenated to build a new feature matrix, generating the final decision by logistic regression. The effectiveness of HDLFCA was validated on both multi-site schizophrenia (SZ, n ∼ 1100) and public autism datasets (ABIDE, n ∼ 1522) by outperforming 12 alternative models at 2.8-8.9% accuracy, including 8 models using either static FNC or TCs and 4 models using dynamic FNC. Appreciable classification accuracy was achieved for HC vs. SZ (85.3%) and HC vs. Autism (72.4%) respectively. More importantly, the most group-discriminative brain regions can be easily attributed and visualized, providing meaningful biological interpretability and highlighting the great potential of the proposed HDLFCA model in the identification of valid neuroimaging biomarkers.

Signal peptide replacements enhance expression and secretion of hepatitis C virus envelope glycoproteins.

A large number of researches focused on glycoproteins E1 and E2 of hepatitis C virus (HCV) aimed at the development of anti-HCV vaccines and inhibitors. Enhancement of E1/E2 expression and secretion is critical for the characterization of these glycoproteins and thus for subunit vaccine development. In this study, we designed and synthesized three signal peptide sequences based on online programs SignalP, TargetP, and PSORT, then removed and replaced the signal peptide preceding E1/E2 by overlapping the polymerase chain reaction method. We assessed the effect of this alteration on E1/E2 expression and secretion in mammalian cells, using western blot analysis, dot blot, and Galanthus nivalis agglutinin lectin capture enzyme immunoassay. Replacing the peptides preceding E1 and E2 with the signal peptides of the tissue plasminogen activator and Gaussia luciferase resulted in maximum enhancement of E1/E2 expression and secretion of E1 in mammalian cells, without altering glycosylation. Such an advance would help to facilitate both the research of E1/E2 biology and the development of an effective HCV subunit vaccine. The strategy used in this study could be applied to the expression and production of other glycoproteins in mammalian cell line-based systems.

Brain imaging-based machine learning in autism spectrum disorder: methods and applications.

Autism spectrum disorder (ASD) is a neurodevelopmental condition with early childhood onset and high heterogeneity. As the pathogenesis is still elusive, ASD diagnosis is comprised of a constellation of behavioral symptoms. Non-invasive brain imaging techniques, such as magnetic resonance imaging (MRI), provide a valuable objective measurement of the brain. Many efforts have been devoted to developing imaging-based diagnostic tools for ASD based on machine learning (ML) technologies. In this survey, we review recent advances that utilize machine learning approaches to classify individuals with and without ASD. First, we provide a brief overview of neuroimaging-based ASD classification studies, including the analysis of publications and general classification pipeline. Next, representative studies are highlighted and discussed in detail regarding different imaging modalities, methods and sample sizes. Finally, we highlight several common challenges and provide recommendations on future directions. In summary, identifying discriminative biomarkers for ASD diagnosis is challenging, and further establishing more comprehensive datasets and dissecting the individual and group heterogeneity will be critical to achieve better ADS diagnosis performance. Machine learning methods will continue to be developed and are poised to help advance the field in this regard.

Altered Effective Brain Connectivity During Habituation in First Episode Schizophrenia With Auditory Verbal Hallucinations: A Dichotic Listening EEG Study.

Background: Habituation is considered to have protective and filtering mechanisms. The present study is aim to find the casual relationship and mechanisms of excitatory-inhibitory (E/I) dysfunctions in schizophrenia (SCZ) via habituation. Methods: A dichotic listening paradigm was performed with simultaneous EEG recording on 22 schizophrenia patients and 22 gender- and age-matched healthy controls. Source reconstruction and dynamic causal modeling (DCM) analysis were performed to estimate the effective connectivity and casual relationship between frontal and temporal regions before and after habituation. Results: The schizophrenia patients expressed later habituation onset (p < 0.01) and hyper-activity in both lateral frontal-temporal cortices than controls (p = 0.001). The patients also showed decreased top-down and bottom-up connectivity in bilateral frontal-temporal regions (p < 0.01). The contralateral frontal-frontal and temporal-temporal connectivity showed a left to right decreasing (p < 0.01) and right to left strengthening (p < 0.01). Conclusions: The results give causal evidence for E/I imbalance in schizophrenia during dichotic auditory processing. The altered effective connectivity in frontal-temporal circuit could represent the trait bio-marker of schizophrenia with auditory hallucinations.

BNCPL: Brain-Network-based Convolutional Prototype Learning for Discriminating Depressive Disorders.

Deep learning has shown great potential to adaptively learn hidden patterns from high dimensional neuroimaging data, so as to extract subtle group differences. Motivated by the convolutional neural networks and prototype learning, we developed a brain-network-based convolutional prototype learning model (BNCPL), which can learn representations that simultaneously maximize inter-class separation while minimize within-class distance. When applying BNCPL to distinguish 208 depressive disorders from 210 healthy controls using resting-state functional connectivity (FC), we achieved an accuracy of 71.0% in multi-site pooling classification (3 sites), with 2.4-7.2% accuracy increase compared to 3 traditional classifiers and 2 alternative deep neural networks. Saliency map was also used to examine the most discriminative FCs learned by the model; the prefrontal-subcortical circuits were identified, which were also correlated with disease severity and cognitive ability. In summary, by integrating convolutional prototype learning and saliency map, we improved both the model interpretability and classification performance, and found that the dysregulation of the functional prefrontal-subcortical circuit may play a pivotal role in discriminating depressive disorders from healthy controls.

Functional network connectivity (FNC)-based generative adversarial network (GAN) and its applications in classification of mental disorders.

As a popular deep learning method, generative adversarial networks (GAN) have achieved outstanding performance in multiple classifications and segmentation tasks. However, the application of GANs to fMRI data is relatively rare. In this work, we proposed a functional network connectivity (FNC) based GAN for classifying psychotic disorders from healthy controls (HCs), in which FNC matrices were calculated by correlation of time courses derived from non-artefactual fMRI independent components (ICs). The proposed GAN model consisted of one discriminator (real FNCs) and one generator (fake FNCs), each has four fully-connected layers. The generator was trained to match the discriminator in the intermediate layers while simultaneously a new objective loss was determined for the generator to improve the whole classification performance. In a case for classifying 269 major depressive disorder (MDD) patients from 286 HCs, an average accuracy of 70.1% was achieved in 10-fold cross-validation, with at least 6% higher compared to the other 6 popular classification approaches (54.5-64.2%). In another application to discriminating 558 schizophrenia patients from 542 HCs from 7 sites, the proposed GAN model achieved 80.7% accuracy in leave-one-site-out prediction, outperforming support vector machine (SVM) and deep neural net (DNN) by 3%-6%. More importantly, we are able to identify the most contributing FNC nodes and edges with the strategy of leave-one-FNC-out recursively. To the best of our knowledge, this is the first attempt to apply the GAN model on the FNC-based classification of mental disorders. Such a framework promises wide utility and great potential in neuroimaging biomarker identification.

Discriminating schizophrenia using recurrent neural network applied on time courses of multi-site FMRI data.

BACKGROUND: Current fMRI-based classification approaches mostly use functional connectivity or spatial maps as input, instead of exploring the dynamic time courses directly, which does not leverage the full temporal information. METHODS: Motivated by the ability of recurrent neural networks (RNN) in capturing dynamic information of time sequences, we propose a multi-scale RNN model, which enables classification between 558 schizophrenia and 542 healthy controls by using time courses of fMRI independent components (ICs) directly. To increase interpretability, we also propose a leave-one-IC-out looping strategy for estimating the top contributing ICs. FINDINGS: Accuracies of 83·2% and 80·2% were obtained respectively for the multi-site pooling and leave-one-site-out transfer classification. Subsequently, dorsal striatum and cerebellum components contribute the top two group-discriminative time courses, which is true even when adopting different brain atlases to extract time series. INTERPRETATION: This is the first attempt to apply a multi-scale RNN model directly on fMRI time courses for classification of mental disorders, and shows the potential for multi-scale RNN-based neuroimaging classifications. FUND: Natural Science Foundation of China, the Strategic Priority Research Program of the Chinese Academy of Sciences, National Institutes of Health Grants, National Science Foundation.

Deep Chronnectome Learning via Full Bidirectional Long Short-Term Memory Networks for MCI Diagnosis.

Brain functional connectivity (FC) extracted from resting-state fMRI (RS-fMRI) has become a popular approach for disease diagnosis, where discriminating subjects with mild cognitive impairment (MCI) from normal controls (NC) is still one of the most challenging problems. Dynamic functional connectivity (dFC), consisting of time-varying spatiotemporal dynamics, may characterize "chronnectome" diagnostic information for improving MCI classification. However, most of the current dFC studies are based on detecting discrete major "brain status" via spatial clustering, which ignores rich spatiotemporal dynamics contained in such chronnectome. We propose Deep Chronnectome Learning for exhaustively mining the comprehensive information, especially the hidden higher-level features, i.e., the dFC time series that may add critical diagnostic power for MCI classification. To this end, we devise a new Fully-connected bidirectional Long Short-Term Memory (LSTM) network (Full-BiLSTM) to effectively learn the periodic brain status changes using both past and future information for each brief time segment and then fuse them to form the final output. We have applied our method to a rigorously built large-scale multi-site database (i.e., with 164 data from NCs and 330 from MCIs, which can be further augmented by 25 folds). Our method outperforms other state-of-the-art approaches with an accuracy of 73.6% under solid cross-validations. We also made extensive comparisons among multiple variants of LSTM models. The results suggest high feasibility of our method with promising value also for other brain disorder diagnoses.

Research on the Mechanism of Cross-species Infection and Transmission for Animal-origin Emerging and Re-emerging Zoonosis Has Won Support by the National Key Research and Development Program of China.

Emerging and re-emerging zoonotic diseases caused by pathogens such as Middle East respiratory syndrome coronavirus (MERS-CoV), West Nile virus (WNV) or Chikungunya virus (CHIKV) pose considerable threats to public health worldwide. Research on the mechanism of cross-species infection and transmission for animal-origin emerging and re-emerging zoonosis (2016YFD0500300) has won support by the National Key Research and Development Program of China. Professor Wenjie Tan (National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention) was the primary principal investigator of this research group. Focusing on the mechanism of transmission and infection for emerging and re-emerging zoonosis, this research will provide an important. foundation for the prevention and control of zoonosis.

[Consecutive five-year follow-up analysis of specific IgG antibody of 22 cases of SARS patients after recovery].

To study IgG antibody persistence and temporal change in SARS coronavirus (SARS-CoV) infected patients, 22 patients recovered from SARS in Beijing were recruited and followed-up from 2004 to 2008, serum samples from patients were collected every year. We checked and analyzed the SARS-CoV IgG antibody (Ab) for five consecutive years using the commercial ELISA test kit. The results showed that: all of the serum were SARS-IgG antibody-positive the first year after recovery, the titer of most serum remained at high levels at the 2ed and 3rd year post infection. The Ab titers significantly declined at 4th year post infection. The IgG Ab was almost undetectable after 5 years post infection. In conclusion, SARS-CoV IgG Ab can be maintained for more than 3 years post infection, however, the titer of IgG Ab has declined markedly 4 years later. These data provide a useful reference for diagnosis and control of SARS infection, the evaluation of immune response and vaccine efficacy.