Brain connectivity in positive and negative syndrome schizophrenia.

Accepted versio

State-space model with deep learning for functional dynamics estimation in resting-state fMRI

Studies on resting-state functional Magnetic Resonance Imaging (rs-fMRI) have shown that different brain regions still actively interact with each other while a subject is at rest, and such functional interaction is not stationary but changes over time. In terms of a large-scale brain network, in this paper, we focus on time-varying patterns of functional networks, i.e., functional dynamics, inherent in rs-fMRI, which is one of the emerging issues along with the network modelling. Specifically, we propose a novel methodological architecture that combines deep learning and state-space modelling, and apply it to rs-fMRI based Mild Cognitive Impairment (MCI) diagnosis. We first devise a Deep Auto-Encoder (DAE) to discover hierarchical non-linear functional relations among regions, by which we transform the regional features into an embedding space, whose bases are complex functional networks. Given the embedded functional features, we then use a Hidden Markov Model (HMM) to estimate dynamic characteristics of functional networks inherent in rs-fMRI via internal states, which are unobservable but can be inferred from observations statistically. By building a generative model with an HMM, we estimate the likelihood of the input features of rs-fMRI as belonging to the corresponding status, i.e., MCI or normal healthy control, based on which we identify the clinical label of a testing subject. In order to validate the effectiveness of the proposed method, we performed experiments on two different datasets and compared with state-of-the-art methods in the literature. We also analyzed the functional networks learned by DAE, estimated the functional connectivities by decoding hidden states in HMM, and investigated the estimated functional connectivities by means of a graph-theoretic approach

SEARCHING NEUROIMAGING BIOMARKERS IN MENTAL DISORDERS WITH GRAPH AND MULTIMODAL FUSION ANALYSIS OF FUNCTIONAL CONNECTIVITY

Mental disorders such as schizophrenia (SZ), bipolar (BD), and major depression disorders (MDD) can cause severe symptoms and life disruption. They share some symptoms, which can pose a major clinical challenge to their differentiation. Objective biomarkers based on neuroimaging may help to improve diagnostic accuracy and facilitate optimal treatment for patients. Over the last decades, non-invasive in-vivo neuroimaging techniques such as magnetic resonance imaging (MRI) have been increasingly applied to measure structure and function in human brains. With functional MRI (fMRI) or structural MRI (sMRI), studies have identified neurophysiological deficits in patients’ brain from different perspective. Functional connectivity (FC) analysis is an approach that measures functional integration in brains. By assessing the temporal coherence of the hemodynamic activity among brain regions, FC is considered capable of characterizing the large-scale integrity of neural activity. In this work, we present two data analysis frameworks for biomarker detection on brain imaging with FC, 1) graph analysis of FC and 2) multimodal fusion analysis, to better understand the human brain. Graph analysis reveals the interaction among brain regions based on graph theory, while the multimodal fusion framework enables us to utilize the strength of different imaging modalities through joint analysis. Four applications related to FC using these frameworks were developed. First, FC was estimated using a model-based approach, and revealed altered the small-world network structure in SZ. Secondly, we applied graph analysis on functional network connectivity (FNC) to differentiate BD and MDD during resting-state. Thirdly, two functional measures, FNC and fractional amplitude of low frequency fluctuations (fALFF), were spatially overlaid to compare the FC and spatial alterations in SZ. And finally, we utilized a multimodal fusion analysis framework, multi-set canonical correlation analysis + joint independent component analysis (mCCA+jICA) to link functional and structural abnormalities in BD and MDD. We also evaluated the accuracy of predictive diagnosis through classifiers generated on the selected features. In summary, via the two frameworks, our work has made several contributions to advance FC analysis, which improves our understanding of underlying brain function and structure, and our findings may be ultimately useful for the development of biomarkers of mental disease

Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

Approaches For Capturing Time-Varying Functional Network Connectivity With Application to Normative Development and Mental Illness

Since the beginning of medical science, the human brain has remained an unsolved puzzle; an illusive organ that controls everything- from breathing to heartbeats, from emotion to anger, and more. With the power of advanced neuroimaging techniques, scientists have now started to solve this nearly impossible puzzle, piece by piece. Over the past decade, various in vivo techniques, including functional magnetic resonance imaging (fMRI), have been increasingly used to understand brain functions. fMRI is extensively being used to facilitate the identification of various neuropsychological disorders such as schizophrenia (SZ), bipolar disorder (BP) and autism spectrum disorder (ASD). These disorders are currently diagnosed based on patients’ self-reported experiences, and observed symptoms and behaviors over the course of the illnesses. Therefore, efficient identification of biological-based markers (biomarkers) can lead to early diagnosis of these mental disorders, and provide a trajectory for disease progression. By applying advanced machine learning techniques on fMRI data, significant differences in brain function among patients with mental disorders and healthy controls can be identified. Moreover, by jointly estimating information from multiple modalities, such as, functional brain data and genetic factors, we can now investigate the relationship between brain function and genes. Functional connectivity (FC) has become a very common measure to characterize brain functions, where FC is defined as the temporal covariance of neural signals between multiple spatially distinct brain regions. Recently, researchers are studying the FC among functionally specialized brain networks which can be defined as a higher level of FC, and is termed as functional network connectivity (FNC, defined as the correlation value that summarizes the overall connection between brain ‘networks’ over time). Most functional connectivity studies have made the limiting assumption that connectivity is stationary over multiple minutes, and ignore to identify the time-varying and reoccurring patterns of FNC among brain regions (known as time-varying FNC). In this dissertation, we demonstrate the use of time-varying FNC features as potential biomarkers to differentiate between patients with mental disorders and healthy subjects. The developmental characteristics of time-varying FNC in children with typically developing brain and ASD have been extensively studies in a cross-sectional framework, and age-, sex- and disease-related FNC profiles have been proposed. Also, time-varying FNC is characterized in healthy adults and patients with severe mental disorders (SZ and BP). Moreover, an efficient classification algorithm is designed to identify patients and controls at individual level. Finally, a new framework is proposed to jointly utilize information from brain’s functional network connectivity and genetic features to find the associations between them. The frameworks that we presented here can help us understand the important role played by time-varying FNC to identify potential biomarkers for the diagnosis of severe mental disorders

New Approaches for Data-mining and Classification of Mental Disorder in Brain Imaging Data

Brain imaging data are incredibly complex and new information is being learned as approaches to mine these data are developed. In addition to studying the healthy brain, new approaches for using this information to provide information about complex mental illness such as schizophrenia are needed. Functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) are two well-known neuroimaging approaches that provide complementary information, both of which provide a huge amount of data that are not easily modelled. Currently, diagnosis of mental disorders is based on a patients self-reported experiences and observed behavior over the longitudinal course of the illness. There is great interest in identifying biologically based marker of illness, rather than relying on symptoms, which are a very indirect manifestation of the illness. The hope is that biological markers will lead to earlier diagnosis and improved treatment as well as reduced costs. Understanding mental disorders is a challenging task due to the complexity of brain structure and function, overlapping features between disorders, small numbers of data sets for training, heterogeneity within disorders, and a very large amount of high dimensional data. This doctoral work proposes machine learning and data mining based algorithms to detect abnormal functional network connectivity patterns of patients with schizophrenia and distinguish them from healthy controls using 1) independent components obtained from task related fMRI data, 2) functional network correlations based on resting-state and a hierarchy of tasks, and 3) functional network correlations in both fMRI and MEG data. The abnormal activation patterns of the functional network correlation of patients are characterized by using a statistical analysis and then used as an input to classification algorithms. The framework presented in this doctoral study is able to achieve good characterization of schizophrenia and provides an initial step towards designing an objective biological marker-based diagnostic test for schizophrenia. The methods we develop can also help us to more fully leverage available imaging technology in order to better understand the mystery of the human brain, the most complex organ in the human body

Hierarchical Bayesian Inference in Psychosis

Schizophrenia is a severe mental illness that affects millions of people worldwide and can have a drastic impact on a patient’s life. The illness is characterised by symptoms such as hallucinations and delusions. In recent years, a powerful theoretical framework has been developed to understand better how such symptoms emerge, the predictive coding account of psychosis. In this thesis, I cast different symptoms of psychosis as instances of hierarchical Bayesian inference in a series of studies. The first study examined the question of how persecutory delusions emerge in early psychosis. We derived hypotheses based on previous literature and simulations and tested them empirically in a sample of 18 first-episode psychosis patients, 19 individuals at clinical high risk for psychosis (CHR) and 19 matched healthy controls (HC). Our results suggest that emerging psychosis may be accompanied by an altered perception of environmental volatility. In a second study, this modelling approach was applied to delusions more broadly in a large dataset including 261 patients with psychotic disorders and 56 HC to examine the relationship between delusions and reasoning biases that were previously reported in psychosis. The results of this study suggest that beliefs of patients with psychotic disorders were characterised by increased belief instability, which explained increased belief updating in light of disconfirmatory evidence. We also assessed the clinical utility of this approach by testing its ability to predict treatment response to a psychotherapeutic intervention and found that the parameters of the computational model were able to predict treatment outcome in individual patients. Lastly, in a final study, we modelled brain activity during an implicit sensory learning task in a third independent sample of 38 CHR, 18 early-illness schizophrenia patients, and 44 HC to assess the biological plausibility of this approach. Our results suggest that hierarchical precision-weighted prediction errors derived from the model modulate electroencephalography (EEG) amplitudes. Moreover, we found not only differences in the expression of precision-weighted prediction errors between schizophrenia patients and HC, but also between CHR, who later converted to a psychotic disorder, and non-converters. Jointly, this work demonstrates that this computational approach may not only be conceptually useful to understand the computational mechanisms underlying psychosis, but also clinically relevant and biologically plausible