Symptom-guided multimodal neuroimage fusion patterns in children with attention-deficit/hyperactivity disorder and its potential "brain structure-function-cognition-behavior" pathological pathways.

The "brain-cognition-behavior" process is an important pathological pathway in children with attention-deficit/hyperactivity disorder (ADHD). Symptom guided multimodal neuroimaging fusion can capture behaviorally relevant and intrinsically linked structural and functional features, which can help to construct a systematic model of the pathology. Analyzing the multimodal neuroimage fusion pattern and exploring how these brain features affect executive function (EF) and leads to behavioral impairment is the focus of this study. Based on gray matter volume (GMV) and fractional amplitude of low frequency fluctuation (fALFF) for 152 ADHD and 102 healthy controls (HC), the total symptom score (TO) was set as a reference to identify co-varying components. Based on the correlation between the identified co-varying components and EF, further mediation analysis was used to explore the relationship between brain image features, EF and clinical symptoms. This study found that the abnormalities of GMV and fALFF in ADHD are mainly located in the default mode network (DMN) and prefrontal-striatal-cerebellar circuits, respectively. GMV in ADHD influences the TO through Metacognition Index, while fALFF in HC mediates the TO through behavior regulation index (BRI). Further analysis revealed that GMV in HC influences fALFF, which further modulates BRI and subsequently affects hyperactivity-impulsivity score. To conclude, structural brain abnormalities in the DMN in ADHD may affect local brain function in the prefrontal-striatal-cerebellar circuit, making it difficult to regulate EF in terms of inhibit, shift, and emotional control, and ultimately leading to hyperactive-impulsive behavior.

Aberrant brain functional and structural developments in MECP2 duplication rats.

Transgenic animal models with homologous etiology provide a promising way to pursue the neurobiological substrates of the behavioral deficits in autism spectrum disorder (ASD). Gain-of-function mutations of MECP2 cause MECP2 duplication syndrome, a severe neurological disorder with core symptoms of ASD. However, abnormal brain developments underlying the autistic-like behavioral deficits of MECP2 duplication syndrome are rarely investigated. To this end, a human MECP2 duplication (MECP2-DP) rat model was created by the bacterial artificial chromosome transgenic method. Functional and structural magnetic resonance imaging (MRI) with high-field were performed on 16 male MECP2-DP rats and 15 male wildtype rats at postnatal 28 days, 42 days, and 56 days old. Multimodal fusion analyses guided by locomotor-relevant metrics and social novelty time separately were applied to identify abnormal brain networks associated with diverse behavioral deficits induced by MECP2 duplication. Aberrant functional developments of a core network primarily composed of the dorsal medial prefrontal cortex (dmPFC) and retrosplenial cortex (RSP) were detected to associate with diverse behavioral phenotypes in MECP2-DP rats. Altered developments of gray matter volume were detected in the hippocampus and thalamus. We conclude that gain-of-function mutations of MECP2 induce aberrant functional activities in the default-mode-like network and aberrant volumetric changes in the brain, resulting in autistic-like behavioral deficits. Our results gain critical insights into the biomarker of MECP2 duplication syndrome and the neurobiological underpinnings of the behavioral deficits in ASD.

Multimodal brain deficits shared in early-onset and adult-onset schizophrenia predict positive symptoms regardless of illness stage.

Incidence of schizophrenia (SZ) has two predominant peaks, in adolescent and young adult. Early-onset schizophrenia provides an opportunity to explore the neuropathology of SZ early in the disorder and without the confound of antipsychotic mediation. However, it remains unexplored what deficits are shared or differ between adolescent early-onset (EOS) and adult-onset schizophrenia (AOS) patients. Here, based on 529 participants recruited from three independent cohorts, we explored AOS and EOS common and unique co-varying patterns by jointly analyzing three MRI features: fractional amplitude of low-frequency fluctuations (fALFF), gray matter (GM), and functional network connectivity (FNC). Furthermore, a prediction model was built to evaluate whether the common deficits in drug-naive SZ could be replicated in chronic patients. Results demonstrated that (1) both EOS and AOS patients showed decreased fALFF and GM in default mode network, increased fALFF and GM in the sub-cortical network, and aberrant FNC primarily related to middle temporal gyrus; (2) the commonly identified regions in drug-naive SZ correlate with PANSS positive significantly, which can also predict PANSS positive in chronic SZ with longer duration of illness. Collectively, results suggest that multimodal imaging signatures shared by two types of drug-naive SZ are also associated with positive symptom severity in chronic SZ and may be vital for understanding the progressive schizophrenic brain structural and functional deficits.

Three-way parallel group independent component analysis: Fusion of spatial and spatiotemporal magnetic resonance imaging data.

Advances in imaging acquisition techniques allow multiple imaging modalities to be collected from the same subject. Each individual modality offers limited yet unique views of the functional, structural, or dynamic temporal features of the brain. Multimodal fusion provides effective ways to leverage these complementary perspectives from multiple modalities. However, the majority of current multimodal fusion approaches involving functional magnetic resonance imaging (fMRI) are limited to 3D feature summaries that do not incorporate its rich temporal information. Thus, we propose a novel three-way parallel group independent component analysis (pGICA) fusion method that incorporates the first-level 4D fMRI data (temporal information included) by parallelizing group ICA into parallel ICA via a unified optimization framework. A new variability matrix was defined to capture subject-wise functional variability and then link it to the mixing matrices of the other two modalities. Simulation results show that the three-way pGICA provides highly accurate cross-modality linkage estimation under both weakly and strongly correlated conditions, as well as comparable source estimation under different noise levels. Results using real brain imaging data identified one linked functional-structural-diffusion component associated to differences between schizophrenia and controls. This was replicated in an independent cohort, and the identified components were also correlated with major cognitive domains. Functional network connectivity revealed visual-subcortical and default mode-cerebellum pairs that discriminate between schizophrenia and controls. Overall, both simulation and real data results support the use of three-way pGICA to identify multimodal spatiotemporal links and to pursue the study of brain disorders under a single unifying multimodal framework.

Task-induced brain connectivity promotes the detection of individual differences in brain-behavior relationships.

Although both resting and task-induced functional connectivity (FC) have been used to characterize the human brain and cognitive abilities, the potential of task-induced FCs in individualized prediction for out-of-scanner cognitive traits remains largely unexplored. A recent study Greene et al. (2018) predicted the fluid intelligence scores using FCs derived from rest and multiple task conditions, suggesting that task-induced brain state manipulation improved prediction of individual traits. Here, using a large dataset incorporating fMRI data from rest and 7 distinct task conditions, we replicated the original study by employing a different machine learning approach, and applying the method to predict two reading comprehension-related cognitive measures. Consistent with their findings, we found that task-based machine learning models often outperformed rest-based models. We also observed that combining multi-task fMRI improved prediction performance, yet, integrating the more fMRI conditions can not necessarily ensure better predictions. Compared with rest, the predictive FCs derived from language and working memory tasks were highlighted with more predictive power in predominantly default mode and frontoparietal networks. Moreover, prediction models demonstrated high stability to be generalizable across distinct cognitive states. Together, this replication study highlights the benefit of using task-based FCs to reveal brain-behavior relationships, which may confer more predictive power and promote the detection of individual differences of connectivity patterns underlying relevant cognitive traits, providing strong evidence for the validity and robustness of the original findings.

Electroconvulsive therapy treatment responsive multimodal brain networks.

Electroconvulsive therapy is regarded as the most effective antidepressant treatment for severe and treatment-resistant depressive episodes. Despite the efficacy of electroconvulsive therapy, the neurobiological underpinnings and mechanisms underlying electroconvulsive therapy induced antidepressant effects remain unclear. The objective of this investigation was to identify electroconvulsive therapy treatment responsive multimodal biomarkers with the 17-item Hamilton Depression Rating Scale guided brain structure-function fusion in 118 patients with depressive episodes and 60 healthy controls. Results show that reduced fractional amplitude of low frequency fluctuations in the prefrontal cortex, insula and hippocampus, linked with increased gray matter volume in anterior cingulate, medial temporal cortex, insula, thalamus, caudate and hippocampus represent electroconvulsive therapy responsive covarying functional and structural brain networks. In addition, relative to nonresponders, responder-specific electroconvulsive therapy related brain networks occur in frontal-limbic network and are associated with successful therapeutic outcomes. Finally, electroconvulsive therapy responsive brain networks were unrelated to verbal declarative memory. Using a data-driven, supervised-learning method, we demonstrated that electroconvulsive therapy produces a remodeling of brain functional and structural covariance that was unique to antidepressant symptom response, but not linked to memory impairment.

Parallel group ICA+ICA: Joint estimation of linked functional network variability and structural covariation with application to schizophrenia.

There is growing evidence that rather than using a single brain imaging modality to study its association with physiological or symptomatic features, the field is paying more attention to fusion of multimodal information. However, most current multimodal fusion approaches that incorporate functional magnetic resonance imaging (fMRI) are restricted to second-level 3D features, rather than the original 4D fMRI data. This trade-off is that the valuable temporal information is not utilized during the fusion step. Here we are motivated to propose a novel approach called "parallel group ICA+ICA" that incorporates temporal fMRI information from group independent component analysis (GICA) into a parallel independent component analysis (ICA) framework, aiming to enable direct fusion of first-level fMRI features with other modalities (e.g., structural MRI), which thus can detect linked functional network variability and structural covariations. Simulation results show that the proposed method yields accurate intermodality linkage detection regardless of whether it is strong or weak. When applied to real data, we identified one pair of significantly associated fMRI-sMRI components that show group difference between schizophrenia and controls in both modalities, and this linkage can be replicated in an independent cohort. Finally, multiple cognitive domain scores can be predicted by the features identified in the linked component pair by our proposed method. We also show these multimodal brain features can predict multiple cognitive scores in an independent cohort. Overall, results demonstrate the ability of parallel GICA+ICA to estimate joint information from 4D and 3D data without discarding much of the available information up front, and the potential for using this approach to identify imaging biomarkers to study brain disorders.

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.

Reconfiguration of Structural and Functional Connectivity Coupling in Patient Subgroups With Adolescent Depression.

Importance: Adolescent major depressive disorder (MDD) is associated with serious adverse implications for brain development and higher rates of self-injury and suicide, raising concerns about its neurobiological mechanisms in clinical neuroscience. However, most previous studies regarding the brain alterations in adolescent MDD focused on single-modal images or analyzed images of different modalities separately, ignoring the potential role of aberrant interactions between brain structure and function in the psychopathology. Objective: To examine alterations of structural and functional connectivity (SC-FC) coupling in adolescent MDD by integrating both diffusion magnetic resonance imaging (MRI) and resting-state functional MRI data. Design, Setting, and Participants: This cross-sectional study recruited participants aged 10 to 18 years from January 2, 2020, to December 28, 2021. Patients with first-episode MDD were recruited from the outpatient psychiatry clinics at The First Affiliated Hospital of Chongqing Medical University. Healthy controls were recruited by local media advertisement from the general population in Chongqing, China. The sample was divided into 5 subgroup pairs according to different environmental stressors and clinical characteristics. Data were analyzed from January 10, 2022, to February 20, 2023. Main Outcomes and Measures: The SC-FC coupling was calculated for each brain region of each participant using whole-brain SC and FC. Primary analyses included the group differences in SC-FC coupling and clinical symptom associations between SC-FC coupling and participants with adolescent MDD and healthy controls. Secondary analyses included differences among 5 types of MDD subgroups: with or without suicide attempt, with or without nonsuicidal self-injury behavior, with or without major life events, with or without childhood trauma, and with or without school bullying. Results: Final analyses examined SC-FC coupling of 168 participants with adolescent MDD (mean [mean absolute deviation (MAD)] age, 16.0 [1.7] years; 124 females [73.8%]) and 101 healthy controls (mean [MAD] age, 15.1 [2.4] years; 61 females [60.4%]). Adolescent MDD showed increased SC-FC coupling in the visual network, default mode network, and insula (Cohen d ranged from 0.365 to 0.581; false discovery rate [FDR]-corrected P < .05). Some subgroup-specific alterations were identified via subgroup analyses, particularly involving parahippocampal coupling decrease in participants with suicide attempt (partial η2 = 0.069; 90% CI, 0.025-0.121; FDR-corrected P = .007) and frontal-limbic coupling increase in participants with major life events (partial η2 ranged from 0.046 to 0.068; FDR-corrected P < .05). Conclusions and Relevance: Results of this cross-sectional study suggest increased SC-FC coupling in adolescent MDD, especially involving hub regions of the default mode network, visual network, and insula. The findings enrich knowledge of the aberrant brain SC-FC coupling in the psychopathology of adolescent MDD, underscoring the vulnerability of frontal-limbic SC-FC coupling to external stressors and the parahippocampal coupling in shaping future-minded behavior.

Data-driven multimodal fusion: approaches and applications in psychiatric research.

In the era of big data, where vast amounts of information are being generated and collected at an unprecedented rate, there is a pressing demand for innovative data-driven multi-modal fusion methods. These methods aim to integrate diverse neuroimaging perspectives to extract meaningful insights and attain a more comprehensive understanding of complex psychiatric disorders. However, analyzing each modality separately may only reveal partial insights or miss out on important correlations between different types of data. This is where data-driven multi-modal fusion techniques come into play. By combining information from multiple modalities in a synergistic manner, these methods enable us to uncover hidden patterns and relationships that would otherwise remain unnoticed. In this paper, we present an extensive overview of data-driven multimodal fusion approaches with or without prior information, with specific emphasis on canonical correlation analysis and independent component analysis. The applications of such fusion methods are wide-ranging and allow us to incorporate multiple factors such as genetics, environment, cognition, and treatment outcomes across various brain disorders. After summarizing the diverse neuropsychiatric magnetic resonance imaging fusion applications, we further discuss the emerging neuroimaging analyzing trends in big data, such as N-way multimodal fusion, deep learning approaches, and clinical translation. Overall, multimodal fusion emerges as an imperative approach providing valuable insights into the underlying neural basis of mental disorders, which can uncover subtle abnormalities or potential biomarkers that may benefit targeted treatments and personalized medical interventions.

Functional Imaging Derived ADHD Biotypes Based on Deep Clustering May Guide Personalized Medication Therapy.

Attention deficit hyperactivity disorder (ADHD) is one prevalent neurodevelopmental disorder with childhood onset, however, there is no clear correspondence established between clinical ADHD subtypes and primary medications. Identifying objective and reliable neuroimaging markers for categorizing ADHD biotypes may lead to more individualized, biotype-guided treatment. Here we proposed graph convolutional network plus deep clustering for ADHD biotype detection using functional network connectivity (FNC), resulting in two biotypes based on 1069 ADHD patients selected from Adolescent Brain and Cognitive Development (ABCD) study, which were well replicated on independent ADHD adolescents undergoing longitudinal medication treatment (n=130). Interestingly, in addition to differences in cognitive performance and hyperactivity/impulsivity symptoms, biotype 1 treated with methylphenidate demonstrated significantly better recovery than biotype 2 treated with atomoxetine (p<0.05, FDR corrected). This imaging-driven, biotype-guided approach holds promise for facilitating personalized treatment of ADHD, exploring possible boundaries through innovative deep learning algorithms aimed at improving medication treatment effectiveness.

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.

A Neuroimaging Signature of Cognitive Aging from Whole-Brain Functional Connectivity.

Cognitive decline is amongst one of the most commonly reported complaints during normal aging. Despite evidence that age and cognition are linked with similar neural correlates, no previous studies have directly ascertained how these two constructs overlap in the brain in terms of neuroimaging-based prediction. Based on a long lifespan healthy cohort (CamCAN, aged 19-89 years, n = 567), it is shown that both cognitive function (domains spanning executive function, emotion processing, motor function, and memory) and human age can be reliably predicted from unique patterns of functional connectivity, with models generalizable in two external datasets (n = 533 and n = 453). Results show that cognitive decline and normal aging both manifest decrease within-network connections (especially default mode and ventral attention networks) and increase between-network connections (somatomotor network). Whereas dorsal attention network is an exception, which is highly predictive on cognitive ability but is weakly correlated with aging. Further, the positively weighted connections in predicting fluid intelligence significantly mediate its association with age. Together, these findings offer insights into why normal aging is often associated with cognitive decline in terms of brain network organization, indicating a process of neural dedifferentiation and compensational theory.

Abnormal Dynamic Functional Network Connectivity Estimated from Default Mode Network Predicts Symptom Severity in Major Depressive Disorder.

Background: Major depressive disorder (MDD) is a severe mental illness marked by a continuous sense of sadness and a loss of interest. The default mode network (DMN) is a group of brain areas that are more active during rest and deactivate when engaged in task-oriented activities. The DMN of MDD has been found to have aberrant static functional network connectivity (FNC) in recent studies. In this work, we extend previous findings by evaluating dynamic functional network connectivity (dFNC) within the DMN subnodes in MDD. Methods: We analyzed resting-state functional magnetic resonance imaging data of 262 patients with MDD and 277 healthy controls (HCs). We estimated dFNCs for seven subnodes of the DMN, including the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and precuneus (PCu), using a sliding window approach, and then clustered the dFNCs into five brain states. Classification of MDD and HC subjects based on state-specific FC was performed using a logistic regression classifier. Transition probabilities between dFNC states were used to identify relationships between symptom severity and dFNC data in MDD patients. Results: By comparing state-specific FNC between HC and MDD, a disrupted connectivity pattern was observed within the DMN. In more detail, we found that the connectivity of ACC is stronger, and the connectivity between PCu and PCC is weaker in individuals with MDD than in those of HC subjects. In addition, MDD showed a higher probability of transitioning from a state with weaker ACC connectivity to a state with stronger ACC connectivity, and this abnormality is associated with symptom severity. This is the first research to look at the dFC of the DMN in MDD with a large sample size. It provides novel evidence of abnormal time-varying DMN configuration in MDD and offers links to symptom severity in MDD subjects. Impact Statement This study is the first attempt that explored the temporal change on default mode network (DMN) connectivity in a relatively large cohort of patients with major depressive disorder (MDD). We also introduced a new hypothesis that explains the inconsistency in DMN functional network connectivity (FNC) comparison between MDD and healthy control based on static FNC in the previous literature. Additionally, our findings suggest that within anterior cingulate cortex connectivity and the connectivity between the precuneus and posterior cingulate cortex are the potential biomarkers for the future intervention of MDD.

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.

Reward Processing in Novelty Seekers: A Transdiagnostic Psychiatric Imaging Biomarker.

BACKGROUND: Dysfunctional reward processing is implicated in multiple mental disorders. Novelty seeking (NS) assesses preference for seeking novel experiences, which is linked to sensitivity to reward environmental cues. METHODS: A subset of 14-year-old adolescents (IMAGEN) with the top 20% ranked high-NS scores was used to identify high-NS-associated multimodal components by supervised fusion. These features were then used to longitudinally predict five different risk scales for the same and unseen subjects (an independent dataset of subjects at 19 years of age that was not used in predictive modeling training at 14 years of age) (within IMAGEN, n ≈1100) and even for the corresponding symptom scores of five types of patient cohorts (non-IMAGEN), including drinking (n = 313), smoking (n = 104), attention-deficit/hyperactivity disorder (n = 320), major depressive disorder (n = 81), and schizophrenia (n = 147), as well as to classify different patient groups with diagnostic labels. RESULTS: Multimodal biomarkers, including the prefrontal cortex, striatum, amygdala, and hippocampus, associated with high NS in 14-year-old adolescents were identified. The prediction models built on these features are able to longitudinally predict five different risk scales, including alcohol drinking, smoking, hyperactivity, depression, and psychosis for the same and unseen 19-year-old adolescents and even predict the corresponding symptom scores of five types of patient cohorts. Furthermore, the identified reward-related multimodal features can classify among attention-deficit/hyperactivity disorder, major depressive disorder, and schizophrenia with an accuracy of 87.2%. CONCLUSIONS: Adolescents with higher NS scores can be used to reveal brain alterations in the reward-related system, implicating potential higher risk for subsequent development of multiple disorders. The identified high-NS-associated multimodal reward-related signatures may serve as a transdiagnostic neuroimaging biomarker to predict disease risks or severity.

Visualizing Functional Network Connectivity Difference between Healthy Control and Major Depressive Disorder Using an Explainable Machine-learning Method.

Major depressive disorder (MDD) is a complex mental disorder characterized by a persistent sad feeling and depressed mood. Recent studies reported differences between healthy control (HC) and MDD by looking to brain networks including default mode and cognitive control networks. More recently there has been interest in studying the brain using advanced machine learning-based classification approaches. However, interpreting the model used in the classification between MDD and HC has not been explored yet. In the current study, we classified MDD from HC by estimating whole-brain connectivity using several classification methods including support vector machine, random forest, XGBoost, and convolutional neural network. In addition, we leveraged the SHapley Additive exPlanations (SHAP) approach as a feature learning method to model the difference between these two groups. We found a consistent result among all classification method in regard of the classification accuracy and feature learning. Also, we highlighted the role of other brain networks particularly visual and sensory motor network in the classification between MDD and HC subjects.

Common and unique multimodal covarying patterns in autism spectrum disorder subtypes.

BACKGROUND: The heterogeneity inherent in autism spectrum disorder (ASD) presents a substantial challenge to diagnosis and precision treatment. Heterogeneity across biological etiologies, genetics, neural systems, neurocognitive attributes and clinical subtypes or phenotypes has been observed across individuals with ASD. METHODS: In this study, we aim to investigate the heterogeneity in ASD from a multimodal brain imaging perspective. The Autism Diagnostic Observation Schedule (ADOS) was used as a reference to guide functional and structural MRI fusion. DSM-IV-TR diagnosed Asperger's disorder (n = 79), pervasive developmental disorder-not otherwise specified [PDD-NOS] (n = 58) and Autistic disorder (n = 92) from ABIDE II were used as discovery cohort, and ABIDE I (n = 400) was used for replication. RESULTS: Dorsolateral prefrontal cortex and superior/middle temporal cortex are the primary common functional-structural covarying cortical brain areas shared among Asperger's, PDD-NOS and Autistic subgroups. Key differences among the three subtypes are negative functional features within subcortical brain areas, including negative putamen-parahippocampus fractional amplitude of low-frequency fluctuations (fALFF) unique to the Asperger's subtype; negative fALFF in anterior cingulate cortex unique to PDD-NOS subtype; and negative thalamus-amygdala-caudate fALFF unique to the Autistic subtype. Furthermore, each subtype-specific brain pattern is correlated with different ADOS subdomains, with social interaction as the common subdomain. The identified subtype-specific patterns are only predictive for ASD symptoms manifested in the corresponding subtypes, but not the other subtypes. CONCLUSIONS: Although ASD has a common neural basis with core deficits linked to social interaction, each ASD subtype is strongly linked to unique brain systems and subdomain symptoms, which may help to better understand the underlying mechanisms of ASD heterogeneity from a multimodal neuroimaging perspective. LIMITATIONS: This study is male based, which cannot be generalized to the female or the general ASD population.

NR4A1 Methylation Associated Multimodal Neuroimaging Patterns Impaired in Temporal Lobe Epilepsy.

DNA hypermethylation has been widely observed in temporal lobe epilepsy (TLE), in which NR4A1 knockdown has been reported to be able to alleviate seizure severity in mouse model, while the underlying methylation-imaging pathway modulated by aberrant methylation levels of NR4A1 remains to be clarified in patients with TLE. Here, using multi-site canonical correlation analysis with reference, methylation levels of NR4A1 in blood were used as priori to guide fusion of three MRI features: functional connectivity (FC), fractional anisotropy (FA), and gray matter volume (GMV) for 56 TLE patients and 65 healthy controls. Post-hoc correlations were further evaluated between the identified NR4A1-associated brain components and disease onset. Results suggested that higher NR4A1 methylation levels in TLE were related with impaired temporal-cerebellar and occipital-cerebellar FC strength, lower FA in cingulum (hippocampus), and reduced GMV in putamen, temporal pole, and cerebellum. Moreover, findings were also replicated well in both patient subsets with either right TLE or left TLE only. Particularly, right TLE patients showed poorer cognitive abilities and more severe brain impairment than left TLE patients, especially more reduced GMV in thalamus. In summary, this work revealed a potential imaging-methylation pathway modulated by higher NR4A1 methylation in TLE via data mining, which may impact the above-mentioned multimodal brain circuits and was also associated with earlier disease onset and more cognitive deficits.

The relevance of transdiagnostic shared networks to the severity of symptoms and cognitive deficits in schizophrenia: a multimodal brain imaging fusion study.

Schizophrenia (SZ) is frequently concurrent with substance use, depressive symptoms, social communication and attention deficits. However, the relationship between common brain networks (e.g., SZ vs. substance use, SZ vs. depression, SZ vs. developmental disorders) with SZ on specific symptoms and cognition is unclear. Symptom scores were used as a reference to guide fMRI-sMRI fusion for SZ (n = 94), substance use with drinking (n = 313), smoking (n = 104), major depressive disorder (MDD, n = 260), developmental disorders with autism spectrum disorder (ASD, n = 421) and attention-deficit/hyperactivity disorder (ADHD, n = 244) respectively. Common brain regions were determined by overlapping the symptom-related components between SZ and these other groups. Correlation between the identified common brain regions and cognition/symptoms in an independent SZ dataset (n = 144) was also performed. Results show that (1): substance use was related with cognitive deficits in schizophrenia through gray matter volume (GMV) in anterior cingulate cortex and thalamus; (2) depression was linked to PANSS negative dimensions and reasoning in SZ through a network involving caudate-thalamus-middle/inferior temporal gyrus in GMV; (3) developmental disorders pattern was correlated with poor attention, speed of processing and reasoning in SZ through inferior temporal gyrus in GMV. This study reveals symptom driven transdiagnostic shared networks between SZ and other mental disorders via multi-group data mining, indicating that some potential common underlying brain networks associated with schizophrenia differently with respect to symptoms and cognition. These results have heuristic value and advocate specific approaches to refine available treatment strategies for comorbid conditions in schizophrenia.