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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.

Background: Functional magnetic resonance imaging (fMRI) is a brain imaging technique that provides detailed insights into brain function and its disruption in various brain disorders. The data-driven analysis of fMRI brain activity maps involves several postprocessing steps, the first of which is identifying whether the estimated brain network maps capture signals of interest, for example, intrinsic connectivity networks (ICNs), or artifacts. This is followed by linking the ICNs to standardized anatomical and functional parcellations. Optionally, as in the study of functional network connectivity (FNC), rearranging the connectivity graph is also necessary to facilitate interpretation. Methods: Here we develop a novel and efficient method (Autolabeler) for implementing and integrating all of these processes in a fully automated manner. The Autolabeler method is pretrained on a cross-validated elastic-net regularized general linear model from the noisecloud toolbox to separate neuroscientifically meaningful ICNs from artifacts. It is capable of automatically labeling activity maps with labels from several well-known anatomical and functional parcellations. Subsequently, this method also maximizes the modularity within functional domains to generate a more systematically structured FNC matrix for post hoc network analyses. Results: Results show that our pretrained model achieves 86% accuracy at classifying ICNs from artifacts in an independent validation data set. The automatic anatomical and functional labels also have a high degree of similarity with manual labels selected by human raters. Discussion: At a time of ever-increasing rates of generating brain imaging data and analyzing brain activity, the proposed Autolabeler method is intended to automate such analyses for faster and more reproducible research. IMPACT STATEMENT: Our proposed method is capable of implementing and integrating some of the crucial tasks in functional magnetic resonance imaging (fMRI) studies. It is the first to incorporate such tasks without the need for expert intervention. We develop an open-source toolbox for the proposed method that can function as stand-alone software and additionally provides seamless integration with the widely used group independent component analysis for fMRI toolbox (GIFT). This integration can aid investigators to conduct fMRI studies in an end-to-end automated manner.

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.

Background: Alzheimer's disease (AD) is a chronic neurodegenerative disorder frequently accompanied by cerebral small vessel disease (CSVD). However, the influence of CSVD on the brain functional connectivity in subjects along the AD continuum is still largely unknown. The current study combined the static and dynamic functional network connectivity (FNC) to explore the underlying mechanism. Materials and Methods: In this study, we included 182 healthy controls, 27 individuals with subjective cognitive decline (SCD), 27 with SCD+CSVD, 104 with mild cognitive impairment (MCI), 123 with MCI+CSVD, 16 with AD, and 62 with AD+CSVD. We examined the static and dynamic FNC within the default mode, salience, and cognitive control domains. We also assessed the association between atypical FNC patterns and cognitive impairments, as well as the pathologies. Results: Static FNC results showed progressively increased within-domain connectivity and decreased between-domain connectivity along the AD continuum, especially in CSVD subjects. Dynamic FNC in CSVD subjects showed more occurrences in a highly modularized state and fewer occurrences in the diffusely connected state. Further analysis showed that neuropathology and CSVD burden divergently affect the FNC changes. Conclusions: The overall results demonstrate divergent abnormalities of FNC in CSVD and non-CSVD individuals along the AD continuum, which were divergently affected by neuropathology and CSVD burden. Specifically, those with CSVD show more static and dynamic FNC impairments, associated with cognitive decline. These findings may advance our understanding of the effect of CSVD on AD onset and progression, and provide potential hints for clinical treatment. IMPACT STATEMENT: By combining the static and dynamic brain functional network connectivity (FNC), our study explored the effect of vascular pathology on FNC in subjects along the Alzheimer's disease (AD) continuum. Results demonstrate divergent FNC abnormalities in individuals with/without cerebral small vessel disease (CSVD) along the AD continuum, which could be divergently affected by neuropathology (amyloid and tau) and CSVD burden. Notably, AD-continuum subjects with CSVD show more static and dynamic FNC impairments, associated with cognitive decline. Conclusively, these findings may advance our understanding of the effect of vascular pathology on AD onset and progression, and provide potential hints for clinical treatment.

BackgroundThe 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.MethodsIn 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.ResultsDorsolateral 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.ConclusionsAlthough 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.LimitationsThis study is male based, which cannot be generalized to the female or the general ASD population.

The dynamics of the human brain span multiple spatial scales, from connectivity associated with a specific region/network to the global organization, each representing different brain mechanisms. Yet brain reconfigurations at different spatial scales are seldom explored and whether they are associated with the neural aspects of brain disorders is far from understood. In this study, we introduced a dynamic measure called step‐wise functional network reconfiguration (sFNR) to characterize how brain configuration rewires at different spatial scales. We applied sFNR to two independent datasets, one includes 160 healthy controls (HCs) and 151 patients with schizophrenia (SZ) and the other one includes 314 HCs and 255 individuals with autism spectrum disorder (ASD). We found that both SZ and ASD have increased whole‐brain sFNR and sFNR between cerebellar and subcortical/sensorimotor domains. At the ICN level, the abnormalities in SZ are mainly located in ICNs within subcortical, sensory, and cerebellar domains, while the abnormalities in ASD are more widespread across domains. Interestingly, the overlap SZ‐ASD abnormality in sFNR between cerebellar and sensorimotor domains was correlated with the reasoning‐problem‐solving performance in SZ (r = −.1652, p = .0058) as well as the Autism Diagnostic Observation Schedule in ASD (r = .1853, p = .0077). Our findings suggest that dynamic reconfiguration deficits may represent a key intersecting point for SZ and ASD. The investigation of brain dynamics at different spatial scales can provide comprehensive insights into the functional reconfiguration, which might advance our knowledge of cognitive decline and other pathophysiology in brain disorders., In this study, we found that both schizophrenia and autism have increased whole‐brain dynamic network reconfiguration and increased dynamic network reconfiguration associated with cerebellar and subcortical/sensorimotor domains. Interestingly, the diseases' overlapping abnormality in dynamic network reconfiguration between cerebellar and sensorimotor domains was correlated with the reasoning‐problem‐solving performance in schizophrenia as well as the Autism Diagnostic Observation Schedule in autism. Our findings suggest that dynamic functional connectivity deficits may represent a key intersecting point for schizophrenia and autism.

Given the dynamic nature of the brain, there has always been a motivation to move beyond ‘static’ functional connectivity, which characterizes functional interactions over an extended period of time. Progress in data acquisition and advances in analytical neuroimaging methods now allow us to assess the whole brain’s dynamic functional connectivity (dFC) and its network-based analog, dynamic functional network connectivity at the macroscale (mm) using fMRI. This has resulted in the rapid growth of analytical approaches, some of which are very complex, requiring technical expertise that could daunt researchers and neuroscientists. Meanwhile, making real progress toward understanding the association between brain dynamism and brain disorders can only be achieved through research conducted by domain experts, such as neuroscientists and psychiatrists. This article aims to provide a gentle introduction to the application of dFC. We first explain what dFC is and the circumstances under which it can be used. Next, we review two major categories of analytical approaches to capture dFC. We discuss caveats and considerations in dFC analysis. Finally, we walk readers through an openly accessible toolbox to capture dFC properties and briefly review some of the dynamic metrics calculated using this toolbox.

Exploring brain changes across the human lifespan is becoming an important topic in neuroscience. Though there are multiple studies which investigated the relationship between age and brain imaging, the results are heterogeneous due to small sample sizes and relatively narrow age ranges. Here, based on year‐wise estimation of 5,967 subjects from 13 to 72 years old, we aimed to provide a more precise description of adult lifespan variation trajectories of gray matter volume (GMV), structural network correlation (SNC), and functional network connectivity (FNC) using independent component analysis and multivariate linear regression model. Our results revealed the following relationships: (a) GMV linearly declined with age in most regions, while parahippocampus showed an inverted U‐shape quadratic relationship with age; SNC presented a U‐shape quadratic relationship with age within cerebellum, and inverted U‐shape relationship primarily in the default mode network (DMN) and frontoparietal (FP) related correlation. (b) FNC tended to linearly decrease within resting‐state networks (RSNs), especially in the visual network and DMN. Early increase was revealed between RSNs, primarily in FP and DMN, which experienced a decrease at older ages. U‐shape relationship was also revealed to compensate for the cognition deficit in attention and subcortical related connectivity at late years. (c) The link between middle occipital gyrus and insula, as well as precuneus and cerebellum, exhibited similar changing trends between SNC and FNC across the adult lifespan. Collectively, these results highlight the benefit of lifespan study and provide a precise description of age‐related regional variation and SNC/FNC changes based on a large dataset.

Functional connectivity (FC) studies have demonstrated the overarching value of studying the brain and its disorders through the undirected weighted graph of fMRI correlation matrix. Most of the work with the FC, however, depends on the way the connectivity is computed, and further depends on the manual post-hoc analysis of the FC matrices. In this work we propose a deep learning architecture BrainGNN that learns the connectivity structure as part of learning to classify subjects. It simultaneously applies a graphical neural network to this learned graph and learns to select a sparse subset of brain regions important to the prediction task. We demonstrate the model's state-of-the-art classification performance on a schizophrenia fMRI dataset and demonstrate how introspection leads to disorder relevant findings. The graphs learned by the model exhibit strong class discrimination and the sparse subset of relevant regions are consistent with the schizophrenia literature., Accepted at Algorithms 2021, 14(3), 75

Background: Alzheimer's disease (AD) is the most common age-related dementia that promotes a decline in memory, thinking, and social skills. The initial stages of dementia can be associated with mi...

Psychosis disorders share overlapping symptoms and are characterized by a wide-spread breakdown in functional brain integration. Although neuroimaging studies have identified numerous connectivity abnormalities in affective and non-affective psychoses, whether they have specific or unique connectivity abnormalities, especially within the early stage is still poorly understood. The early phase of psychosis is a critical period with fewer chronic confounds and when treatment intervention may be most effective. In this work, we examined whole-brain functional network connectivity (FNC) from both static and dynamic perspectives in patients with affective psychosis (PAP) or with non-affective psychosis (PnAP) and healthy controls (HCs). A fully automated independent component analysis (ICA) pipeline called “Neuromark” was applied to high-quality functional magnetic resonance imaging (fMRI) data with 113 early-phase psychosis patients (32 PAP and 81 PnAP) and 52 HCs. Relative to the HCs, both psychosis groups showed common abnormalities in static FNC (sFNC) between the thalamus and sensorimotor domain, and between subcortical regions and the cerebellum. PAP had specifically decreased sFNC between the superior temporal gyrus and the paracentral lobule, and between the cerebellum and the middle temporal gyrus/inferior parietal lobule. On the other hand, PnAP showed increased sFNC between the fusiform gyrus and the superior medial frontal gyrus. Dynamic FNC (dFNC) was investigated using a combination of a sliding window approach, clustering analysis, and graph analysis. Three reoccurring brain states were identified, among which both psychosis groups had fewer occurrences in one antagonism state (state 2) and showed decreased network efficiency within an intermediate state (state 1). Compared with HCs and PnAP, PAP also showed a significantly increased number of state transitions, indicating more unstable brain connections in affective psychosis. We further found that the identified connectivity features were associated with the overall positive and negative syndrome scale, an assessment instrument for general psychopathology and positive symptoms. Our findings support the view that subcortical-cortical information processing is disrupted within five years of the initial onset of psychosis and provide new evidence that abnormalities in both static and dynamic connectivity consist of shared and unique features for the early affective and non-affective psychoses.

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.

ObjectiveTo investigate the dynamic functional connectivity of thalamocortical networks in interictal migraine patients and whether clinical features are associated with abnormal connectivity.MethodsWe investigated dynamic functional network connectivity (dFNC) of the migraine brain in 89 interictal migraine patients and 70 healthy controls. We focused on the temporal properties of thalamocortical connectivity using sliding window cross-correlation, clustering state analysis, and graph-theory methods. Relationships between clinical symptoms and abnormal dFNC were evaluated using a multivariate linear regression model.ResultsFive dFNC brain states were identified to characterize and compare dynamic functional connectivity patterns. We demonstrated that migraineurs spent more time in a strongly interconnected between-network state, but they spent less time in a sparsely connected state. Interestingly, we found that abnormal posterior thalamus (pulvinar nucleus) dFNC with the visual cortex and the precuneus were significantly correlated with headache frequency of migraine. Further topologic measures revealed that migraineurs had significantly lower efficiency of information transfer in both global and local dFNC.ConclusionOur results demonstrated a transient pathologic state with atypical thalamocortical connectivity in migraineurs and extended current findings regarding abnormal thalamocortical networks and dysrhythmia in migraine.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with social communication deficits and restricted/repetitive behaviors and is characterized by large-scale atypical subcortical-cortical connectivity, including impaired resting-state functional connectivity between thalamic and sensory regions. Previous studies have typically focused on the abnormal static connectivity in ASD and overlooked potential valuable dynamic patterns in brain connectivity. However, resting-state brain connectivity is indeed highly dynamic, and abnormalities in dynamic brain connectivity have been widely identified in psychiatric disorders. In this study, we investigated the dynamic functional network connectivity (dFNC) between 51 intrinsic connectivity networks in 170 individuals with ASD and 195 age-matched typically developing (TD) controls using independent component analysis and a sliding window approach. A hard clustering state analysis and a fuzzy meta-state analysis were conducted respectively, for the exploration of local and global aberrant dynamic connectivity patterns in ASD. We examined the group difference in dFNC between thalamic and sensory networks in each functional state and group differences in four high-dimensional dynamic measures. The results showed that compared with TD controls, individuals with ASD show an increase in transient connectivity between hypothalamus/subthalamus and some sensory networks (right postcentral gyrus, bi paracentral lobule, and lingual gyrus) in certain functional states, and diminished global meta-state dynamics of the whole-brain functional network. In addition, these atypical dynamic patterns are significantly associated with autistic symptoms indexed by the Autism Diagnostic Observation Schedule. These converging results support and extend previous observations regarding hyperconnectivity between thalamic and sensory regions and stable whole-brain functional configuration in ASD. Dynamic brain connectivity may serve as a potential biomarker of ASD and further investigation of these dynamic patterns might help to advance our understanding of behavioral differences in this complex neurodevelopmental disorder.

The analysis of time-varying activity and connectivity patterns (i.e., the chronnectome) using resting-state magnetic resonance imaging has become an important part of ongoing neuroscience discussions. The majority of previous work has focused on variations of temporal coupling among fixed spatial nodes or transition of the dominant activity/connectivity pattern over time. Here, we introduce an approach to capture spatial dynamics within functional domains (FDs), as well as temporal dynamics within and between FDs. The approach models the brain as a hierarchical functional architecture with different levels of granularity, where lower levels have higher functional homogeneity and less dynamic behavior and higher levels have less homogeneity and more dynamic behavior. First, a high-order spatial independent component analysis is used to approximate functional units. A functional unit is a pattern of regions with very similar functional activity over time. Next, functional units are used to construct FDs. Finally, functional modules (FMs) are calculated from FDs, providing an overall view of brain dynamics. Results highlight the spatial fluidity within FDs, including a broad spectrum of changes in regional associations, from strong coupling to complete decoupling. Moreover, FMs capture the dynamic interplay between FDs. Patients with schizophrenia show transient reductions in functional activity and state connectivity across several FDs, particularly the subcortical domain. Activity and connectivity differences convey unique information in many cases (e.g., the default mode) highlighting their complementarity information. The proposed hierarchical model to capture FD spatiotemporal variations provides new insight into the macroscale chronnectome and identifies changes hidden from existing approaches.

Temperament consists of multi-dimensional traits that affect various domains of human life. Evidence has shown functional connectome-based predictive models are powerful predictors of cognitive abilities. Putatively, individuals' innate temperament traits may be predictable by unique patterns of brain functional connectivity (FC) as well. However, quantitative prediction for multiple temperament traits at the individual level has not yet been studied. Therefore, we were motivated to realize the individualized prediction of four temperament traits (novelty seeking [NS], harm avoidance [HA], reward dependence [RD] and persistence [PS]) using whole-brain FC. Specifically, a multivariate prediction framework integrating feature selection and sparse regression was applied to resting-state fMRI data from 360 college students, resulting in 4 connectome-based predictive models that enabled prediction of temperament scores for unseen subjects in cross-validation. More importantly, predictive models for HA and NS could be successfully generalized to two relevant personality traits for unseen individuals, i.e., neuroticism and extraversion, in an independent dataset. In four temperament trait predictions, brain connectivities that show top contributing power commonly concentrated on the hippocampus, prefrontal cortex, basal ganglia, amygdala, and cingulate gyrus. Finally, across independent datasets and multiple traits, we show person's temperament traits can be reliably predicted using functional connectivity strength within frontal-subcortical circuits, indicating that human social and behavioral performance can be characterized by specific brain connectivity profile.

Approaches involving the use of learning architectures on multimodal neuroimaging data tend to assume uniformity in the way information is stored in various sub-domains of the brain, thus not catering to the differences across functional and structural sub-domains. We introduce a learning framework to effectively incorporate multimodal features using structural and functional MRI data from a dataset of schizophrenia patients and controls, accounting for and exploiting the heterogeneity in the sub-domains of the brain. We analyze these sub-domains in terms of their functional interactions (i.e. within and between network connectivity) and structural properties (gray matter volume). By using Bayesian optimization on a search space of flexible multimodal architectures with multiple branches, we demonstrate that the discriminatory information from structural and functional sub-domains can be better recovered if the complexity of subspace structure in the model can be tuned to reflect the extent of non-linearity with which each sub-domain encodes the information. Our repeated cross-validated results from a schizophrenia classification problem show that for better classification and interpretation, sub-domains known for their role or disruption in Schizophrenia require more sophisticated subspace structure in the model compared to others. Our work emphasizes on the requirement to create multimodal frameworks that can adapt based on differences in the way various sub-domains of the brain encode discriminatory information. This is important to not only have better-performing prediction models but also to reveal sub-domains associated with the outcome at hand.

Background: Electroconvulsive therapy (ECT) is one of the most effective treatments for major depressive disorder. Recently, there has been increasing attention to evaluate the effect of ECT on resting-state functional magnetic resonance imaging (rs-fMRI). This study aims to compare rs-fMRI of depressive disorder (DEP) patients with healthy participants, investigate whether pre-ECT dynamic functional network connectivity network (dFNC) estimated from patients rs-fMRI is associated with an eventual ECT outcome, and explore the effect of ECT on brain network states.Method: Resting-state functional magnetic resonance imaging (fMRI) data were collected from 119 patients with depression or depressive disorder (DEP) (76 females), and 61 healthy (HC) participants (34 females), with an age mean of 52.25 (N = 180) years old. The pre-ECT and post-ECT Hamilton Depression Rating Scale (HDRS) were 25.59 ± 6.14 and 11.48 ± 9.07, respectively. Twenty-four independent components from default mode (DMN) and cognitive control network (CCN) were extracted, using group-independent component analysis from pre-ECT and post-ECT rs-fMRI. Then, the sliding window approach was used to estimate the pre-and post-ECT dFNC of each subject. Next, k-means clustering was separately applied to pre-ECT dFNC and post-ECT dFNC to assess three distinct states from each participant. We calculated the amount of time each subject spends in each state, which is called “occupancy rate” or OCR. Next, we compared OCR values between HC and DEP participants. We also calculated the partial correlation between pre-ECT OCRs and HDRS change while controlling for age, gender, and site. Finally, we evaluated the effectiveness of ECT by comparing pre- and post-ECT OCR of DEP and HC participants.Results: The main findings include (1) depressive disorder (DEP) patients had significantly lower OCR values than the HC group in state 2, where connectivity between cognitive control network (CCN) and default mode network (DMN) was relatively higher than other states (corrected p = 0.015), (2) Pre-ECT OCR of state, with more negative connectivity between CCN and DMN components, is linked with the HDRS changes (R = 0.23 corrected p = 0.03). This means that those DEP patients who spent less time in this state showed more HDRS change, and (3) The post-ECT OCR analysis suggested that ECT increased the amount of time DEP patients spent in state 2 (corrected p = 0.03).Conclusion: Our finding suggests that dynamic functional network connectivity (dFNC) features, estimated from CCN and DMN, show promise as a predictive biomarker of the ECT outcome of DEP patients. Also, this study identifies a possible underlying mechanism associated with the ECT effect on DEP patients.

Bipolar disorder and schizophrenia are associated with brain morphometry alterations. This study investigates inter-individual variability in brain structural profiles, both within diagnostic groups and between patients and healthy individuals. Brain morphometric measures from three independent samples of patients with schizophrenia (n = 168), bipolar disorder (n = 122), and healthy individuals (n = 180) were modeled as single vectors to generated individualized profiles of subcortical volumes and regional cortical thickness. These profiles were then used to compute a person-based similarity index (PBSI) for subcortical volumes and for regional cortical thickness, to quantify the within-group similarity of the morphometric profile of each individual to that of the other participants in the same diagnostic group. There was no effect of diagnosis on the PBSI for subcortical volumes. In contrast, compared to healthy individuals, the PBSI for cortical thickness was lower in patients with schizophrenia (effect size = 0.4, p ≤ 0.0002), but not in patients with bipolar disorder. The results were robust and reproducible across samples. We conclude that disease mechanisms for these disorders produce modest inter-individual variations in brain morphometry that should be considered in future studies attempting to cluster patients in subgroups.

Objective: A graph theoretical approach provides a powerful framework for discovering potential biomarkers of psychotic disorders. Comparing the brain graphs of the control and patient groups can help us to discover changes in mental disorders in a more convenient way. In this paper, we propose a novel tool to identify missing links associated with blocked paths (segregation) and new links associated with additional paths (abnormal integration) in estimated patient group’s time-varying graphs. We highlight the approach in an example application to the resting-state functional magnetic resonance imaging (fMRI) data of schizophrenia (SZ) patients. Methods: We first estimated whole-brain functional connectivity dynamics using a combination of spatial independent component analysis (ICA), sliding time window, and k-means clustering of windowed correlation matrices on resting-state fMRI data. The clusters are regarded as functional connectivity states, and each of them includes time intervals exhibiting similar connectivity patterns. We then estimated a Gaussian graphical model (GGM) for each state for both groups. To evaluate this approach, we compared different paths between brain components (nodes) of SZ and control groups’ graphs within each state by using the concept of connected components in graph theory. Results: We identified missing edges associated with disconnectivity (disconnectors) and showed there are additional edges in the SZ group graph that contribute to creating new paths in brain graphs. Conclusion: The proposed approach provides a tool for extracting time-varying graphs and identifying disconnectors associated with disconnectivity (absence of paths) and also connectors associated with abnormal integration (additional paths) in patient group graphs. Significance: We detected several missing links in SZ, both within and between functional domains, in particular within the subcortical (3 links) and somatomotor (4 links) domains. Interestingly, our proposed method identified new links within the somatomotor domain which may be related to a compensatory response in patients that warrants future study.

Understanding the associations of the structural and functional patterns of the brain is vital. Recent studies have focused on utilizing this information within and across the different functional and anatomical domains (i.e., groups of brain networks) using neuroimaging data. In this work, we use a Bayesian optimization-based method known as the Tree Parzen Estimator (TPE) to identify variation in the nature of information encoded by different functional magnetic resonance imaging (fMRI) sub-domains of the brain. We show by repeated cross-validation on a schizophrenia classification task that specific sub-domains may require more sophisticated learning architectures to contribute optimally to classification, while others require less complicated ones. Our findings reveal the need for adaptive, hierarchical learning frameworks catering to features from different sub-domains to optimally identify features enabling the prediction of the outcome of interest.

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.

The human brain is an adaptive system that combines the reconfiguration of brain interactions with the evolution of local brain activities. Reoccurring brain activity and connectivity patterns, regarded as “brain states”, are widely observed via different neuroimaging techniques, revealing new insights into the pathophysiology of multiple brain disorders, such as schizophrenia (SZ). However, previous work fails to depict a comprehensive picture of brain dynamics because they only focus on either brain activity or connectivity dynamics, ignoring the temporal co-evolution between them. Here, we propose an analysis pipeline to capture dynamic brain states with covarying activity-connectivity and apply it SZ datasets to probe disease-related brain abnormalities. Results were consistent across different brain parcellation techniques (independent component analysis and atlas-based analysis) and in two independent cohorts who underwent resting-state fMRI scans. We found that the state-based activity patterns and connectivity patterns show high correspondence, where strong and antagonistic connectivity is typically accompanied by strong low-frequency fluctuations across the whole brain while the weak and sparse connectivity co-occurs with weak low-frequency fluctuations, especially in sub-cortical, sensory and cerebellum regions. In addition, a graphical analysis showed that brain activity-connectivity states have different network efficiency and node efficiency is correlated with the low-frequency activities of brain nodes. Compared with healthy controls (HCs), SZ patients spend more time in weakly-connected and -activated brain states but less time in strongly-connected and -activated brain states. Interestingly, the fractional occupancy of one brain state was correlated with attention performance. SZ patients also showed lower node efficiency in thalamic regions in the “strong” brain states. These robust results extend previous findings in dynamic brain analysis and thalamocortical dysfunction in schizophrenia. Capturing covarying brain activity-connectivity dynamics might help to advance our understanding of the co-evolutionary property of brain network and the underlying mechanism in brain disorders which cannot be observed by focusing either of them along.

Brain structural networks have been shown to consistently organize in functionally meaningful architectures covering the entire brain. However, to what extent brain structural architectures match the intrinsic functional networks in different functional domains remains under explored. In this study, based on independent component analysis, we revealed 45 pairs of structural-functional (S-F) component maps, distributing across nine functional domains, in both a discovery cohort (n = 6005) and a replication cohort (UK Biobank, n = 9214), providing a well-match multimodal spatial map template for public use. Further network module analysis suggested that unimodal cortical areas (e.g., somatomotor and visual networks) indicate higher S-F coherence, while heteromodal association cortices, especially the frontoparietal network (FPN), exhibit more S-F divergence. Collectively, these results suggest that the expanding and maturing brain association cortex demonstrates a higher degree of changes compared with unimodal cortex, which may lead to higher interindividual variability and lower S-F coherence.

Previous successes of deep learning (DL) approaches on several complex tasks have hugely inflated expectations of their power to learn subtle properties of complex brain imaging data, and scale to large datasets. Perhaps as a reaction to this inflation, recent critical commentaries unfavorably compare DL with standard machine learning (SML) approaches for the analysis of brain imaging data. Yet, their conclusions are based on pre-engineered features which deprives DL of its main advantage: representation learning. Here we evaluate this and show the importance of representation learning for DL performance on brain imaging data. We report our findings from a large-scale systematic comparison of SML approaches versus DL profiled in a ten-way age and gender-based classification task on 12,314 structural MRI images. Results show that DL methods, if implemented and trained following the prevalent DL practices, have the potential to substantially improve compared to SML approaches. We also show that DL approaches scale particularly well presenting a lower asymptotic complexity in relative computational time, despite being more complex. Our analysis reveals that the performance improvement saturates as the training sample size grows, but shows significantly higher performance throughout. We also show evidence that the superior performance of DL is primarily due to the excellent representation learning capabilities and that SML methods can perform equally well when operating on representations produced by the trained DL models. Finally, we demonstrate that DL embeddings span a comprehensible projection spectrum and that DL consistently localizes discriminative brain biomarkers, providing an example of the robustness of prediction relevance estimates. Our findings highlight the presence of non-linearities in brain imaging data that DL frameworks can exploit to generate superior predictive representations for characterizing the human brain, even with currently available data sizes.

The interactions among brain entities, commonly computed through pair-wise functional connectivity, are assumed to be manifestations of information processing which drive function. However, this focus on large-scale networks and their pair-wise temporal interactions is likely missing important information contained within fMRI data. We propose leveraging multi-connected features at both the voxel- and network-level to capture “multi-way entanglement” between networks and voxels, providing improved resolution of interconnected brain functional hierarchy. Entanglement refers to each brain network being heavily enmeshed with the activity of other networks. Under our multi-connectivity assumption, elements of a system simultaneously communicate and interact with each other through multiple pathways. As such we move beyond the typical pair-wise temporal partial or full correlation. We propose a framework to estimate functional multi-connectivity (FMC) by computing the relationship between system-wide connections of intrinsic connectivity networks (ICNs). Results show that FMC obtains information which is different from standard pair-wise analyses.

Schizophrenia (SZ) is a severe neuropsychiatric disorder with a hallmark of functional dysconnectivity between numerous brain regions. With an implicit assumption of stationary brain interactions during the scanning period, most of the resting-state functional magnetic resonance imaging (fMRI) studies are conducted on static functional network connectivity (sFNC). Dynamic functional network connectivity (dFNC) that explores temporal patterns of functional connectivity (FC) might provide additional information to its static counterpart. In this work, we first estimate latent features (called connectivity states) by applying k-means clustering on dFNC. Next, using the estimated latent features, we trained and tested a classifier, which can differentiate SZ from healthy control (HC) subjects with 71% accuracy. Using a feature selection method embedded in the classifier, we have highlighted the role of transition probabilities between states as potential biomarkers and identified the role of lightly modularized transient connectivity state in pulling healthy subjects out of both highly modularized and very disconnected states. This will offer some new understandings about the way the healthy brain shifts between the most and the least connected states of whole brain connectivity.

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 etal. (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.

Behavioral changes are the earliest signs of a mental disorder, but arguably, the dynamics of brain function gets affected even earlier. Subsequently, spatio-temporal structure of disorder-specific dynamics is crucial for early diagnosis and understanding the disorder mechanism. A common way of learning discriminatory features relies on training a classifier and evaluating feature importance. Classical classifiers, based on handcrafted features are quite powerful, but suffer the curse of dimensionality when applied to large input dimensions of spatio-temporal data. Deep learning algorithms could handle the problem and a model introspection could highlight discriminatory spatio-temporal regions but need way more samples to train. In this paper we present a novel self supervised training schema which reinforces whole sequence mutual information local to context (whole MILC). We pre-train the whole MILC model on unlabeled and unrelated healthy control data. We test our model on three different disorders (i) Schizophrenia (ii) Autism and (iii) Alzheimers and four different studies. Our algorithm outperforms existing self-supervised pre-training methods and provides competitive classification results to classical machine learning algorithms. Importantly, whole MILC enables attribution of subject diagnosis to specific spatio-temporal regions in the fMRI signal.

The human brain is a highly dynamic system with non-stationary neural activity and rapidly-changing neural interaction. Resting-state dynamic functional connectivity (dFC) has been widely studied during recent years, and the emerging aberrant dFC patterns have been identified as important features of many mental disorders such as schizophrenia (SZ). However, only focusing on the time-varying patterns in FC is not enough, since the local neural activity itself (in contrast to the inter-connectivity) is also found to be highly fluctuating from research using high-temporal-resolution imaging techniques. Exploring the time-varying patterns in brain activity and their relationships with time-varying brain connectivity is important for advancing our understanding of the co-evolutionary property of brain network and the underlying mechanism of brain dynamics. In this study, we introduced a framework for characterizing time-varying brain activity and exploring its associations with time-varying brain connectivity, and applied this framework to a resting-state fMRI dataset including 151 SZ patients and 163 age- and gender matched healthy controls (HCs). In this framework, 48 brain regions were first identified as intrinsic connectivity networks (ICNs) using group independent component analysis (GICA). A sliding window approach was then adopted for the estimation of dynamic amplitude of low-frequency fluctuation (dALFF) and dFC, which were used to measure time-varying brain activity and time-varying brain connectivity respectively. The dALFF was further clustered into six reoccurring states by the k-means clustering method and the group difference in occurrences of dALFF states was explored. Lastly, correlation coefficients between dALFF and dFC were calculated and the group difference in these dALFF-dFC correlations was explored. Our results suggested that 1) ALFF of brain regions was highly fluctuating during the resting-state and such dynamic patterns are altered in SZ, 2) dALFF and dFC were correlated in time and their correlations are altered in SZ. The overall results support and expand prior work on abnormalities of brain activity, static FC (sFC) and dFC in SZ, and provide new evidence on aberrant time-varying brain activity and its associations with brain connectivity in SZ, which might underscore the disrupted brain cognitive functions in this mental disorder.

Individuals at clinical high-risk (CHR) for psychosis are characterized by attenuated psychotic symptoms. Only a minority of CHR individuals convert to full-blown psychosis. Therefore, there is a strong interest in identifying neurobiological abnormalities underlying the psychosis risk syndrome. Dynamic functional connectivity (DFC) captures time-varying connectivity over short time scales, and has the potential to reveal complex brain functional organization. Based on resting-state functional magnetic resonance imaging (fMRI) data from 70 healthy controls (HCs), 53 CHR individuals, and 58 early illness schizophrenia (ESZ) patients, we applied a novel group information guided ICA (GIG-ICA) to estimate inherent connectivity states from DFC, and then investigated group differences. We found that ESZ patients showed more aberrant connectivities and greater alterations than CHR individuals. Results also suggested that disease-related connectivity states occurred in CHR and ESZ groups. Regarding the dominant state with the highest contribution to dynamic connectivity, ESZ patients exhibited greater impairments than CHR individuals primarily in the cerebellum, frontal cortex, thalamus and temporal cortex, while CHR and ESZ populations shared common aberrances mainly in the supplementary motor area, parahippocampal gyrus and postcentral cortex. CHR-specific changes were also found in the connections between the superior frontal gyrus and calcarine cortex in the dominant state. Our findings suggest that CHR individuals generally show an intermediate functional connectivity pattern between HCs and SZ patients but also have unique connectivity alterations.

Privacy concerns for rare disease data, institutional or IRB policies, access to local computational or storage resources or download capabilities are among the reasons that may preclude analyses that pool data to a single site. A growing number of multi-site projects and consortia were formed to function in the federated environment to conduct productive research under constraints of this kind. In this scenario, a quality control tool that visualizes decentralized data in its entirety via global aggregation of local computations is especially important, as it would allow the screening of samples that cannot be jointly evaluated otherwise. To solve this issue, we present two algorithms: decentralized data stochastic neighbor embedding, dSNE, and its differentially private counterpart, DP-dSNE. We leverage publicly available datasets to simultaneously map data samples located at different sites according to their similarities. Even though the data never leaves the individual sites, dSNE does not provide any formal privacy guarantees. To overcome that, we rely on differential privacy: a formal mathematical guarantee that protects individuals from being identified as contributors to a dataset. We implement DP-dSNE with AdaCliP, a method recently proposed to add less noise to the gradients per iteration. We introduce metrics for measuring the embedding quality and validate our algorithms on these metrics against their centralized counterpart on two toy datasets. Our validation on six multi-site neuroimaging datasets shows promising results for the quality control tasks of visualization and outlier detection, highlighting the potential of our private, decentralized visualization approach.

Dimension reduction is essential in fMRI decoding, but the complex relationship between fMRI data and class labels is often unknown or not well modeled so that the most effective dimension reduction (e.d.r.) directions can hardly be identified. In the present study, we introduce a novel fMRI decoding approach based on an effective and general dimension reduction method, namely sliced inverse regression (SIR), which can exploit class information for estimating e.d.r. directions even when the relationship between fMRI data and class labels is not explicitly known. We incorporate singular value decomposition (SVD) into SIR to overcome SIR's limitation in dealing with ultra-high-dimensional data, and integrate SVD-SIR into a pattern classifier to enable quantification of the contributions of fMRI voxels to class labels. The resultant new SIR decoding analysis (SIR-DA) approach is capable of decoding behavioral responses and identifying predictive fMRI patterns. Simulation results showed that SIR-DA can more accurately detect e.d.r. directions and achieve higher classification accuracy than decoding approaches based on conventional dimension reduction methods. Further, we applied SIR-DA on real-world pain-evoked fMRI data to decode the level of pain perception and showed that SIR-DA can achieve higher accuracy in pain prediction than conventional methods. These results suggest that SIR-DA is an effective data-driven technique to decode behavioral or cognitive states from fMRI data and to uncover unknown brain patterns associated with behavior or cognitive responses.

Background Resting-state fMRI (rs-fMRI) is employed to assess “functional connections” of signal between brain regions. However, multiple rs-fMRI paradigms and data-filtering strategies have been used, highlighting the need to explore BOLD signal across the spectrum. Rs-fMRI data is typically filtered at frequencies ranging between 0.008∼0.2 Hz to mitigate nuisance signal (e.g. cardiac, respiratory) and maximize neuronal BOLD signal. However, some argue neuronal BOLD signal may be parsed at higher frequencies. New method To assess the contributions of rs-fMRI along the BOLD spectra on functional network connectivity (FNC) matrices, a spatially constrained independent component analysis (ICA) was performed at seven different frequency “bins”, after which FNC values and FNC measures of matrix-randomness were assessed using linear mixed models. Results Results show FNCs at higher-frequency bins display similar randomness to those from the typical frequency bins (0.01−0.15), while the largest values are in the 0.31−0.46 Hz bin. Eyes open (EO) vs eyes closed (EC) comparison found EC was less random than EO across most frequency bins. Further, FNC was greater in EC across auditory and cognitive control pairings while EO values were greater in somatomotor, visual, and default mode FNC. Comparison with existing methods Effect sizes of frequency and resting-state paradigm vary from small to large, but the most notable results are specific to frequency ranges and resting-state paradigm with artifacts like motion displaying negligible effect sizes. Conclusions These suggest unique information may be derived from FNC matrices across frequencies and paradigms, but additional data is necessary prior to any definitive conclusions.

Exploring brain changes across the human lifespan is becoming an important topic in neuroscience. Though there are multiple studies which investigated the relationship between age and brain imaging data, the results are heterogeneous due to small sample sizes and relatively narrow age ranges. Here, based on year-wise estimation of 5967 subjects from 13 to 72 years old, we aimed to provide a more precise description of adult lifespan variation trajectories of gray matter volume (GMV), structural network correlation (SNC) and functional network connectivity (FNC) using independent component analysis and multivariate linear regression model. Our results revealed the following relationships: 1)GMV linearly declined with age in most regions, while parahippocampus showed an inverted U-shape quadratic relationship with age; SNC presented a U-shape quadratic relationship with age within cerebellum, and inverted U-shape relationship primarily in the default mode network (DMN) and frontoparietal (FP) related correlation. 2) FNC tended to linearly decrease within resting-state networks (RSNs), especially in visual network and DMN. Early increase was revealed between RSNs, primarily in FP and DMN, which experienced decrease at older ages. U-shape relationship was also revealed to compensate for the cognition deficit in attention and subcortical related connectivity at late years. 3) The link between middle occipital gyrus and insula, as well as precuneus and cerebellum, exhibited similar changing trends between SNC and FNC across the adult lifespan. Collectively, these results highlight the benefit of lifespan study and provide a precise description of age-related regional variation and SNC/FNC changes based on a large dataset.

SummaryIncreasing sharing initiatives on neuroimaging data have provided unprecedented opportunities to study brain disorders. Standardized approaches for capturing reproducible and comparable biomarkers are greatly needed. Here, we propose a method, NeuroMark, which leverages a priori-driven independent component analysis to effectively extract functional brain network biomarkers from functional magnetic resonance imaging (fMRI) data. NeuroMark automatically estimates features adaptable to each individual and comparable across subjects by taking advantage of the replicated brain network templates extracted from 1828 healthy controls as guidance to initialize the individual-level networks. Four studies including 2454 subjects were conducted spanning six brain disorders (schizophrenia, autism spectrum disorder, depression, bipolar disorder, mild cognitive impairment and Alzheimer’s disease) to evaluate the proposed method from different perspectives (replication, cross-study comparison, subtle difference identification, and multi-disorder classification). Results demonstrate the great potential of NeuroMark in its feasibility to link different datasets/studies/disorders and enhance sensitivity in identifying biomarkers for patients with challenging mental illnesses.Significance StatementIncreasing evidence highlights that features extracted from resting fMRI data can be leveraged as potential biomarkers of brain disorders. However, it has been difficult to replicate results using different datasets, translate findings across studies, and differentiate brain disorders sharing similar clinical symptoms. It is important to systematically characterize the degree to which unique and similar impaired patterns are reflective of brain disorders. We propose a fully automated method (called NeuroMark) that leverages priori-driven independent component analysis (ICA) using replicated brain network templates to estimate individual-subject network features. Evaluated by four studies involving six different brain disorders, we show that NeuroMark can effectively link the comparison of biomarkers across different studies/datasets/disorders and enable classification between complex brain disorders, while also providing information about relevant aspects of whole brain functional connectivity.

Goyal et al. (1) report in PNAS that the female adult brain has a persistently lower metabolic brain age compared with the male brain at the same chronological age. In interpreting this remarkable finding, the authors propose that sex-related differences in brain development may, in part, play a role in “setting” the female brain at a younger initial brain age at puberty, allowing them to maintain a younger brain throughout adulthood. We argue that this may not be the case and provide evidence to show that, in fact, the opposite may be true during childhood and adolescence. First, according to figure 2A of ref. 1, surprisingly, the predicted age between 35 and 50 y was underestimated for both males and females. It is unclear if the bias in this age range could have affected the overall findings or played a role in only the result from training on males and testing on females surviving a two-sided t test. Moreover, it is unclear … [↵][1]1To whom correspondence should be addressed. Email: nmaleki{at}mgh.harvard.edu. [1]: #xref-corresp-1-1

Background Bipolar disorder (BD) patients show morphological abnormalities in gray matter (GM) and white matter (WM), which can be revealed by structure MRI (sMRI) and diffusion tensor imaging (DTI) respectively. However, previous studies on BD mainly relied on separated analysis of single neuroimaging modality, and it remains unclear how GM and WM covary to the abnormal brain structures of BD patients. Methods We recorded multimodal sMRI-DTI data of 35 BD patients and 30 healthy controls (HC) and used multimodal canonical component analysis and joint independent component analysis (mCCA-jICA) to identify altered covariant structures in GM and WM of BD. Group-discriminative and joint group-discriminative independent components (ICs) were identified between BD and HC. Correlation analysis was performed between the mixing coefficients and behavioral index. Results For BD patients, experiments results revealed that the GM atrophy in inferior frontal gyrus, right anterior cingulate gyrus and left superior frontal gyrus are associated with the WM integrity reduction in corticospinal tract and superior longitudinal fasciculus. Further, compared with HC, different correlation between mixing coefficients of ICs and age was observed for BD patients. Limitations The number of participants needs to be increased to more rigorously validate the results of this study, ideally from multiple sites. Functional imaging data could be utilized to explore structural-functional covariant pattern in BD. Possible confounding effect of medication. Conclusions We performed fusion analysis of sMRI and DTI and revealed covariant (GM-WM) structural patterns of BD patients. This study could be useful for developing more reliable neural biomarkers of BD.

ObjectiveTo identify and validate an fMRI-based neural marker for migraine without aura (MwoA) and to examine its association with treatment response.MethodsWe conducted cross-sectional studies with resting-state fMRI data from 230 participants and machine learning analyses. In studies 1 through 3, we identified, cross-validated, independently validated, and cross-sectionally validated an fMRI-based neural marker for MwoA. In study 4, we assessed the relationship between the neural marker and treatment responses in migraineurs who received a 4-week real or sham acupuncture treatment, or were waitlisted, in a registered clinical trial.ResultsIn study 1 (n = 116), we identified a neural marker with abnormal functional connectivity within the visual, default mode, sensorimotor, and frontal-parietal networks that could discriminate migraineurs from healthy controls (HCs) with 93% sensitivity and 89% specificity. In study 2 (n = 38), we investigated the generalizability of the marker by applying it to an independent cohort of migraineurs and HCs and achieved 84% sensitivity and specificity. In study 3 (n = 76), we verified the specificity of the marker with new datasets of migraineurs and patients with other chronic pain disorders (chronic low back pain and fibromyalgia) and demonstrated 78% sensitivity and 76% specificity for discriminating migraineurs from nonmigraineurs. In study 4 (n = 116), we found that the changes in the marker responses showed significant correlation with the changes in headache frequency in response to real acupuncture.ConclusionWe identified an fMRI-based neural marker that captures distinct characteristics of MwoA and can link disease pattern changes to brain changes.

Arguably, unsupervised learning plays a crucial role in the majority of algorithms for processing brain imaging. A recently introduced unsupervised approach Deep InfoMax (DIM) is a promising tool for exploring brain structure in a flexible non-linear way. In this paper, we investigate the use of variants of DIM in a setting of progression to Alzheimer's disease in comparison with supervised AlexNet and ResNet inspired convolutional neural networks. As a benchmark, we use a classification task between four groups: patients with stable, and progressive mild cognitive impairment (MCI), with Alzheimer's disease, and healthy controls. Our dataset is comprised of 828 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Our experiments highlight encouraging evidence of the high potential utility of DIM in future neuroimaging studies., Accepted to 2019 IEEE Biomedical and Health Informatics (BHI) as a conference paper

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 GICA into a parallel 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 inter-modality 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. 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.

Multimodal fusion is an effective approach to discover covarying patterns of multiple imaging types impaired in brain diseases, such as Autism spectrum disorders (ASD). Compelling evidence has confirmed that social impairment is a primary and common characteristic of ASD. Here, based on a supervised learning strategy and independent component analysis, we used Social Responsiveness Scale (SRS) of participants as reference, to guide the 3-way MRI data fusion, aiming to identify the multimodal brain regions associated with social impairment in ASD. Results show high consistence on the brain patterns identified in two independent cohorts, suggesting that lower fALFF and ReHo values in the default mode network (DMN) and occipital cortex, as well as reduced cortical thickness in inferior frontal and superior temporal cortex were associated with social impairment in autism. Moreover, these multimodal brain regions were also detected in a repeatable manner, validating the robustness of the fusion with reference approach, demonstrating the ability of multimodal fusion to identify potential imaging markers of interest for mental disorders.

Conventionally, brain function is inferred from the magnitude data of the complex-valued fMRI output. Since the fMRI phase image (unwrapped) provides a representation of brain internal magnetic fieldmap (by a constant scale difference), it can also be used to study brain function while providing a more direct representation of the brain's magnetic state. In this study, we collected a cohort of resting-state fMRI magnitude and phase data pairs from 600 subjects (age from 10 to 76, 346 males), decomposed the phase data by group independent component analysis (pICA), calculated the functional network connectivity (pFNC). In comparison with the magnitude-based brain function analysis (mICA and mFNC), we find that the pFNC matrix contains fewer significant functional connections (with p-value thresholding) than the mFNC matrix, which are sparsely distributed across the whole brain with near/far interconnections and positive/negative correlations in rough balance. We also find a few of brain rest sub-networks within the phase data, primarily in subcortical, cerebellar, and visual regions. Overall, our findings offer new insights into brain function connectivity in the context of a focus on the brain's internal magnetic state.

Structural and functional brain abnormalities have been widely identified in dementia, but with variable replicability and significant overlap. Alzheimer's disease (AD) and Binswanger's disease (BD) share similar symptoms and common brain changes that can confound diagnosis. In this study, we aimed to investigate correlated structural and functional brain changes in AD and BD by combining resting-state functional magnetic resonance imaging (fMRI) and diffusion MRI. A group independent component analysis was first performed on the fMRI data to extract 49 intrinsic connectivity networks (ICNs). Then we conducted a multi-set canonical correlation analysis on three features, functional network connectivity (FNC) between ICNs, fractional anisotropy (FA) and mean diffusivity (MD). Two inter-correlated components show significant group differences. The first component demonstrates distinct brain changes between AD and BD. AD shows increased cerebellar FNC but decreased thalamic and hippocampal FNC. Such FNC alterations are linked to the decreased corpus callosum FA. AD also has increased MD in the frontal and temporal cortex, but BD shows opposite alterations. The second component demonstrates specific brain changes in BD. Increased FNC is mainly between default mode and sensory regions, while decreased FNC is mainly within the default mode domain and related to auditory regions. The FNC changes are associated with FA changes in posterior/middle cingulum cortex and visual cortex and increased MD in thalamus and hippocampus. Our findings provide evidence of linked functional and structural deficits in dementia and suggest that AD and BD have both common and distinct changes in white matter integrity and functional connectivity., Highlights • This is the first study to explore multi-modalities changes in different dementia. • A multimodal fusion method is applied to identify joint components. • Brain abnormalities in different modalities are highly correlated. • Alzheimer's and Binswanger's disease share similar brain changes. • Alzheimer's and Binswanger's disease also have distinct brain changes.

Subcortical ischemic vascular disease (SIVD) is a major subtype of vascular dementia with features that overlap clinically with Alzheimer's disease (AD), confounding diagnosis. Neuroimaging is a more specific and biologically based approach for detecting brain changes and thus may help to distinguish these diseases. There is still a lack of knowledge regarding the shared and specific functional brain abnormalities, especially functional connectivity changes in relation to AD and SIVD. In this study, we investigated both static functional network connectivity (sFNC) and dynamic FNC (dFNC) between 54 intrinsic connectivity networks in 19 AD patients, 19 SIVD patients, and 38 age-matched healthy controls. The results show that both patient groups have increased sFNC between the visual and cerebellar (CB) domains but decreased sFNC between the cognitive-control and CB domains. SIVD has specifically decreased sFNC within the sensorimotor domain while AD has specifically altered sFNC between the default-mode and CB domains. In addition, SIVD has more occurrences and a longer dwell time in the weakly connected dFNC states, but with fewer occurrences and a shorter dwell time in the strongly connected dFNC states. AD has both similar and opposite changes in certain dynamic features. More importantly, the dynamic features are found to be associated with cognitive performance. Our findings highlight similar and distinct functional connectivity alterations in AD and SIVD from both static and dynamic perspectives and indicate dFNC to be a more important biomarker for dementia since its progressively altered patterns can better track cognitive impairment in AD and SIVD.

Brain functional networks identified from fMRI data can provide potential biomarkers for brain disorders. Group independent component analysis (GICA) is popular for extracting brain functional networks from multiple subjects. In GICA, different strategies exist for reconstructing subject-specific networks from the group-level networks. However, it is unknown whether these strategies have different sensitivities to group differences and abilities in distinguishing patients. Among GICA, spatio-temporal regression (STR) and spatially constrained ICA approaches such as group information guided ICA (GIG-ICA) can be used to propagate components (indicating networks) to a new subject that is not included in the original subjects. In this study, based on the same a priori network maps, we reconstructed subject-specific networks using these two methods separately from resting-state fMRI data of 151 schizophrenia patients (SZs) and 163 healthy controls (HCs). We investigated group differences in the estimated functional networks and the functional network connectivity (FNC) obtained by each method. The networks were also used as features in a cross-validated support vector machine (SVM) for classifying SZs and HCs. We selected features using different strategies to provide a comprehensive comparison between the two methods. GIG-ICA generally showed greater sensitivity in statistical analysis and better classification performance (accuracy 76.45 ± 8.9%, sensitivity 0.74 ± 0.11, specificity 0.79 ± 0.11) than STR (accuracy 67.45 ± 8.13%, sensitivity 0.65 ± 0.11, specificity 0.71 ± 0.11). Importantly, results were also consistent when applied to an independent dataset including 82 HCs and 82 SZs. Our work suggests that the functional networks estimated by GIG-ICA are more sensitive to group differences, and GIG-ICA is promising for identifying image-derived biomarkers of brain disease., Highlights • We investigate which group ICA method is more sensitive to group differences in networks and FNC. • We evaluate which group ICA method can result in better classification performance. • We compare the spatio-temporal regression (STR) and GIG-ICA using different feature selection and model building strategies and independent samples. • We use different feature selection and model building strategies and classification using independent samples. • Using fMRI data including schizophrenia patients, GIG-ICA shows better performance than the traditional STR method.

Graphical abstract, Highlights • Propose a new pipeline to link brain changes among different datasets, studies, and disorders. • Identify reproducible biomarkers in schizophrenia using independent data. • Find both common and unique brain impairments in schizophrenia and autism. • Reveal gradual changes from healthy controls to mild cognitive impairment to Alzheimer’s disease. • Obtain high classification accuracy (~90%) between bipolar disorder and major depressive disorder., Many mental illnesses share overlapping or similar clinical symptoms, confounding the diagnosis. It is important to systematically characterize the degree to which unique and similar changing patterns are reflective of brain disorders. Increasing sharing initiatives on neuroimaging data have provided unprecedented opportunities to study brain disorders. However, it is still an open question on replicating and translating findings across studies. Standardized approaches for capturing reproducible and comparable imaging markers are greatly needed. Here, we propose a pipeline based on the priori-driven independent component analysis, NeuroMark, which is capable of estimating brain functional network measures from functional magnetic resonance imaging (fMRI) data that can be used to link brain network abnormalities among different datasets, studies, and disorders. NeuroMark automatically estimates features adaptable to each individual subject and comparable across datasets/studies/disorders by taking advantage of the reliable brain network templates extracted from 1828 healthy controls as guidance. Four studies including 2442 subjects were conducted spanning six brain disorders (schizophrenia, autism spectrum disorder, mild cognitive impairment, Alzheimer’s disease, bipolar disorder, and major depressive disorder) to evaluate validity of the proposed pipeline from different perspectives (replication of brain abnormalities, cross-study comparison, identification of subtle brain changes, and multi-disorder classification using identified biomarkers). Our results highlight that NeuroMark effectively identified replicated brain network abnormalities of schizophrenia across different datasets; revealed interesting neural clues on the overlap and specificity between autism and schizophrenia; demonstrated brain functional impairments present to varying degrees in mild cognitive impairments and Alzheimer's disease; and captured biomarkers that achieved good performance in classifying bipolar disorder and major depressive disorder.

Cognitive impairment is a feature of many psychiatric diseases, including schizophrenia. Here we aim to identify multimodal biomarkers for quantifying and predicting cognitive performance in individuals with schizophrenia and healthy controls. A supervised learning strategy is used to guide three-way multimodal magnetic resonance imaging (MRI) fusion in two independent cohorts including both healthy individuals and individuals with schizophrenia using multiple cognitive domain scores. Results highlight the salience network (gray matter, GM), corpus callosum (fractional anisotropy, FA), central executive and default-mode networks (fractional amplitude of low-frequency fluctuation, fALFF) as modality-specific biomarkers of generalized cognition. FALFF features are found to be more sensitive to cognitive domain differences, while the salience network in GM and corpus callosum in FA are highly consistent and predictive of multiple cognitive domains. These modality-specific brain regions define—in three separate cohorts—promising co-varying multimodal signatures that can be used as predictors of multi-domain cognition., Cognitive impairment is a feature of many psychiatric diseases. Here the authors aimed to identify multimodal neuromarkers that can be used to quantify and predict cognitive performance in individuals with schizophrenia using three different features of MRI and three independent cohorts.

Brain functional imaging data, especially functional magnetic resonance imaging (fMRI) data, have been employed to reflect functional integration of the brain. Alteration in brain functional connectivity (FC) is expected to provide potential biomarkers for classifying or predicting brain disorders. In this paper, we present a comprehensive review in order to provide guidance about the available brain FC measures and typical classification strategies. We survey the state-of-the-art FC analysis methods including widely used static functional connectivity (SFC) and more recently proposed dynamic functional connectivity (DFC). Temporal correlations among regions of interest (ROIs), data-driven spatial network and functional network connectivity (FNC) are often computed to reflect SFC from different angles. SFC can be extended to DFC using a sliding-window framework, and intrinsic connectivity states along the time-varying connectivity patterns are typically extracted using clustering or decomposition approaches. We also briefly summarize window-less DFC approaches. Subsequently, we highlight various strategies for feature selection including the filter, wrapper and embedded methods. In terms of model building, we include traditional classifiers as well as more recently applied deep learning methods. Moreover, we review representative applications with remarkable classification accuracy for psychosis and mood disorders, neurodevelopmental disorder, and neurological disorders using fMRI data. Schizophrenia, bipolar disorder, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), Alzheimer's disease and mild cognitive impairment (MCI) are discussed. Finally, challenges in the field are pointed out with respect to the inaccurate diagnosis labeling, the abundant number of possible features and the difficulty in validation. Some suggestions for future work are also provided.

Major depressive disorder (MDD) is a complex mood disorder characterized by persistent and overwhelming depression. Previous studies have identified abnormalities in large scale functional brain networks in MDD, yet most of them were based on static functional connectivity. In contrast, here we explored disrupted topological organization of dynamic functional network connectivity (dFNC) in MDD based on graph theory. One hundred and eighty-two MDD patients and 218 healthy controls were included in this study, all Chinese Han people. By applying group information guided independent component analysis (GIG-ICA) to resting-state functional magnetic resonance imaging (fMRI) data, the dFNCs of each subject were estimated using a sliding window method and k-means clustering. Network properties including global efficiency, local efficiency, node strength and harmonic centrality, were calculated for each subject. Five dynamic functional states were identified, three of which demonstrated significant group differences in their percentage of state occurrence. Interestingly, MDD patients spent much more time in a weakly-connected State 2, which includes regions previously associated with self-focused thinking, a representative feature of depression. In addition, the FNCs in MDD were connected differently in different states, especially among prefrontal, sensorimotor, and cerebellum networks. MDD patients exhibited significantly reduced harmonic centrality primarily involving parietal lobule, lingual gyrus and thalamus. Moreover, three dFNCs with disrupted node properties were commonly identified in different states, and also correlated with depressive symptom severity and cognitive performance. This study is the first attempt to investigate the dynamic functional abnormalities in MDD in a Chinese population using a relatively large sample size, which provides new evidence on aberrant time-varying brain activity and its network disruptions in MDD, which might underscore the impaired cognitive functions in this mental disorder.