MRI Assessment of Cerebral White Matter Microvascular Hemodynamics Across the Adult Lifespan.

BACKGROUND: Changes in cerebral hemodynamics with aging are important for understanding age-related variation in neuronal health. While many prior studies have focused on gray matter, less is known regarding white matter due in part to measurement challenges related to the lower vascular density in white matter. PURPOSE: To investigate the impact of age and sex on white matter hemodynamics in a Human Connectome Project in Aging (HCP-A) cohort using tract-based spatial statistics (TBSS). STUDY TYPE: Retrospective cross-sectional. POPULATION: Six hundred seventy-eight typically aging individuals (381 female), aged 36-100 years. FIELD STRENGTH/SEQUENCE: Multi-delay pseudo-continuous arterial spin labeling (ASL) and diffusion-weighted pulsed-gradient spin-echo echo planar imaging sequences at 3.0 T. ASSESSMENT: A skeleton of mean fractional anisotropy (FA) was produced using TBSS. This skeleton was used to project ASL-derived cerebral blood flow (CBF) and arterial transit time (ATT) measures onto white matter tracts. STATISTICAL TESTS: General linear models were applied to white matter FA, CBF, and ATT maps, while covarying for age and sex. Threshold-free cluster enhancement multiple comparisons correction was performed for the effects of age and sex, thresholded at PFWE < 0.05. CBF, ATT, and FA were compared between sex for each tract using analysis of covariance, with multiple comparisons correction for the number of tracts at PFDR < 0.05. RESULTS: Significantly lower white matter CBF and significantly prolonged white matter ATTs were associated with older age. These effects were widespread across tracts for ATT. Significant (PFDR < 0.05) sex differences in ATT were observed across all tracts, and significant sex differences in CBF were observed in all tracts except the bilateral uncinate fasciculus. Females demonstrated significantly higher CBF compared to males across the lifespan. Few tracts demonstrated significant sex differences in FA. DATA CONCLUSION: This study identified significant sex- and age-associated differences in white matter hemodynamics across tracts. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Associations between age, sex, APOE genotype, and regional vascular physiology in typically aging adults.

Altered blood flow in the human brain is characteristic of typical aging. However, numerous factors contribute to inter-individual variation in patterns of blood flow throughout the lifespan. To better understand the mechanisms behind such variation, we studied how sex and APOE genotype, a primary genetic risk factor for Alzheimer's disease (AD), influence associations between age and brain perfusion measures. We conducted a cross-sectional study of 562 participants from the Human Connectome Project - Aging (36 to >90 years of age). We found widespread associations between age and vascular parameters, where increasing age was associated with regional decreases in cerebral blood flow (CBF) and increases in arterial transit time (ATT). When grouped by sex and APOE genotype, interactions between group and age demonstrated that females had relatively greater CBF and lower ATT compared to males. Females carrying the APOEε4 allele showed the strongest association between CBF decline and ATT incline with age. This demonstrates that sex and genetic risk for AD modulate age-associated patterns of cerebral perfusion measures.

Cardiovascular and metabolic health is associated with functional brain connectivity in middle-aged and older adults: Results from the Human Connectome Project-Aging study.

Several cardiovascular and metabolic indicators, such as cholesterol and blood pressure have been associated with altered neural and cognitive health as well as increased risk of dementia and Alzheimer's disease in later life. In this cross-sectional study, we examined how an aggregate index of cardiovascular and metabolic risk factor measures was associated with correlation-based estimates of resting-state functional connectivity (FC) across a broad adult age-span (36-90+ years) from 930 volunteers in the Human Connectome Project Aging (HCP-A). Increased (i.e., worse) aggregate cardiometabolic scores were associated with reduced FC globally, with especially strong effects in insular, medial frontal, medial parietal, and superior temporal regions. Additionally, at the network-level, FC between core brain networks, such as default-mode and cingulo-opercular, as well as dorsal attention networks, showed strong effects of cardiometabolic risk. These findings highlight the lifespan impact of cardiovascular and metabolic health on whole-brain functional integrity and how these conditions may disrupt higher-order network integrity.

Towards a brain-based predictome of mental illness.

Neuroimaging-based approaches have been extensively applied to study mental illness in recent years and have deepened our understanding of both cognitively healthy and disordered brain structure and function. Recent advancements in machine learning techniques have shown promising outcomes for individualized prediction and characterization of patients with psychiatric disorders. Studies have utilized features from a variety of neuroimaging modalities, including structural, functional, and diffusion magnetic resonance imaging data, as well as jointly estimated features from multiple modalities, to assess patients with heterogeneous mental disorders, such as schizophrenia and autism. We use the term "predictome" to describe the use of multivariate brain network features from one or more neuroimaging modalities to predict mental illness. In the predictome, multiple brain network-based features (either from the same modality or multiple modalities) are incorporated into a predictive model to jointly estimate features that are unique to a disorder and predict subjects accordingly. To date, more than 650 studies have been published on subject-level prediction focusing on psychiatric disorders. We have surveyed about 250 studies including schizophrenia, major depression, bipolar disorder, autism spectrum disorder, attention-deficit hyperactivity disorder, obsessive-compulsive disorder, social anxiety disorder, posttraumatic stress disorder, and substance dependence. In this review, we present a comprehensive review of recent neuroimaging-based predictomic approaches, current trends, and common shortcomings and share our vision for future directions.

A framework for linking resting-state chronnectome/genome features in schizophrenia: A pilot study.

Multimodal, imaging-genomics techniques offer a platform for understanding genetic influences on brain abnormalities in psychiatric disorders. Such approaches utilize the information available from both imaging and genomics data and identify their association. Particularly for complex disorders such as schizophrenia, the relationship between imaging and genomic features may be better understood by incorporating additional information provided by advanced multimodal modeling. In this study, we propose a novel framework to combine features corresponding to functional magnetic resonance imaging (functional) and single nucleotide polymorphism (SNP) data from 61 schizophrenia (SZ) patients and 87 healthy controls (HC). In particular, the features for the functional and genetic modalities include dynamic (i.e., time-varying) functional network connectivity (dFNC) features and the SNP data, respectively. The dFNC features are estimated from component time-courses, obtained using group independent component analysis (ICA), by computing sliding-window functional network connectivity, and then estimating subject specific states from this dFNC data using a k-means clustering approach. For each subject, both the functional (dFNC states) and SNP data are selected as features for a parallel ICA (pICA) based imaging-genomic framework. This analysis identified a significant association between a SNP component (defined by large clusters of functionally related SNPs statistically correlated with phenotype components) and time-varying or dFNC component (defined by clusters of related connectivity links among distant brain regions distributed across discrete dynamic states, and statistically correlated with genomic components) in schizophrenia. Importantly, the polygenetic risk score (PRS) for SZ (computed as a linearly weighted sum of the genotype profiles with weights derived from the odds ratios of the psychiatric genomics consortium (PGC)) was negatively correlated with the significant dFNC component, which were mostly present within a state that exhibited a lower occupancy rate in individuals with SZ compared with HC, hence identifying a potential dFNC imaging biomarker for schizophrenia. Taken together, the current findings provide preliminary evidence for a link between dFNC measures and genetic risk, suggesting the application of dFNC patterns as biomarkers in imaging genetic association study.

Aberrant functional network connectivity in psychopathy from a large (N = 985) forensic sample.

Psychopathy is a personality disorder characterized by antisocial behavior, lack of remorse and empathy, and impaired decision making. The disproportionate amount of crime committed by psychopaths has severe emotional and economic impacts on society. Here we examine the neural correlates associated with psychopathy to improve early assessment and perhaps inform treatments for this condition. Previous resting-state functional magnetic resonance imaging (fMRI) studies in psychopathy have primarily focused on regions of interest. This study examines whole-brain functional connectivity and its association to psychopathic traits. Psychopathy was hypothesized to be characterized by aberrant functional network connectivity (FNC) in several limbic/paralimbic networks. Group-independent component and regression analyses were applied to a data set of resting-state fMRI from 985 incarcerated adult males. We identified resting-state networks (RSNs), estimated FNC between RSNs, and tested their association to psychopathy factors and total summary scores (Factor 1, interpersonal/affective; Factor 2, lifestyle/antisocial). Factor 1 scores showed both increased and reduced functional connectivity between RSNs from seven brain domains (sensorimotor, cerebellar, visual, salience, default mode, executive control, and attentional). Consistent with hypotheses, RSNs from the paralimbic system-insula, anterior and posterior cingulate cortex, amygdala, orbital frontal cortex, and superior temporal gyrus-were related to Factor 1 scores. No significant FNC associations were found with Factor 2 and total PCL-R scores. In summary, results suggest that the affective and interpersonal symptoms of psychopathy (Factor 1) are associated with aberrant connectivity in multiple brain networks, including paralimbic regions.

Connectivity dynamics in typical development and its relationship to autistic traits and autism spectrum disorder.

Recent advances in neuroimaging techniques have provided significant insights into developmental trajectories of human brain function. Characterizations of typical neurodevelopment provide a framework for understanding altered neurodevelopment, including differences in brain function related to developmental disorders and psychopathology. Historically, most functional connectivity studies of typical and atypical development operate under the assumption that connectivity remains static over time. We hypothesized that relaxing stationarity assumptions would reveal novel features of both typical brain development related to children on the autism spectrum. We employed a "chronnectomic" (recurring, time-varying patterns of connectivity) approach to evaluate transient states of connectivity using resting-state functional MRI in a population-based sample of 774 6- to 10-year-old children. Dynamic connectivity was evaluated using a sliding-window approach, and revealed four transient states. Internetwork connectivity increased with age in modularized dynamic states, illustrating an important pattern of connectivity in the developing brain. Furthermore, we demonstrated that higher levels of autistic traits and ASD diagnosis were associated with longer dwell times in a globally disconnected state. These results provide a roadmap to the chronnectomic organization of the developing brain and suggest that characteristics of functional brain connectivity are related to children on the autism spectrum.

Classification of schizophrenia and bipolar patients using static and dynamic resting-state fMRI brain connectivity.

Recently, functional network connectivity (FNC, defined as the temporal correlation among spatially distant brain networks) has been used to examine the functional organization of brain networks in various psychiatric illnesses. Dynamic FNC is a recent extension of the conventional FNC analysis that takes into account FNC changes over short periods of time. While such dynamic FNC measures may be more informative about various aspects of connectivity, there has been no detailed head-to-head comparison of the ability of static and dynamic FNC to perform classification in complex mental illnesses. This paper proposes a framework for automatic classification of schizophrenia, bipolar and healthy subjects based on their static and dynamic FNC features. Also, we compare cross-validated classification performance between static and dynamic FNC. Results show that the dynamic FNC significantly outperforms the static FNC in terms of predictive accuracy, indicating that features from dynamic FNC have distinct advantages over static FNC for classification purposes. Moreover, combining static and dynamic FNC features does not significantly improve the classification performance over the dynamic FNC features alone, suggesting that static FNC does not add any significant information when combined with dynamic FNC for classification purposes. A three-way classification methodology based on static and dynamic FNC features discriminates individual subjects into appropriate diagnostic groups with high accuracy. Our proposed classification framework is potentially applicable to additional mental disorders.

Brain structural indicators of ß-amyloid neuropathology.

Recent efforts demonstrated the efficacy of identifying early-stage neuropathology of Alzheimer's disease (AD) through lumbar puncture cerebrospinal fluid assessment and positron emission tomography (PET) radiotracer imaging. These methods are effective yet are invasive, expensive, and not widely accessible. We extend and improve the multiscale structural mapping (MSSM) procedure to develop structural indicators of ß-amyloid neuropathology in preclinical AD, by capturing both macrostructural and microstructural properties throughout the cerebral cortex using a structural MRI. We find that the MSSM signal is regionally altered in clear positive and negative cases of preclinical amyloid pathology (N = 220) when cortical thickness alone or hippocampal volume is not. It exhibits widespread effects of amyloid positivity across the posterior temporal, parietal, and medial prefrontal cortex, surprisingly consistent with the typical pattern of amyloid deposition. The MSSM signal is significantly correlated with amyloid PET in almost half of the cortex, much of which overlaps with regions where beta-amyloid accumulates, suggesting it could provide a regional brain 'map' that is not available from systemic markers such as plasma markers.

Feasibility of common, enjoyable game play for assessing daily cognitive functioning in older adults.

Background: Frequent digital monitoring of cognition is a promising approach for assessing endpoints in prevention and treatment trials of Alzheimer's disease and related dementias (ADRD). This study evaluated the feasibility of the MIND GamePack© for recurrent semi-passive assessment of cognition across a longitudinal interval. Methods: The MIND GamePack consists of four iPad-based games selected to be both familiar and enjoyable: Word Scramble, Block Drop, FreeCell, and Memory Match. Participants were asked to play 20 min/day for 5 days (100 min) for 4 months. Feasibility of use by older adults was assessed by measuring gameplay time and game performance. We also evaluated compliance through semi-structured surveys. A linear generalized estimating equation (GEE) model was used to analyze changes in gameplay time, and a regression tree model was employed to estimate the days it took for game performance to plateau. Subjective and environmental factors associated with gameplay time and performance were examined, including daily self-reported questions of memory and thinking ability, mood, sleep, energy, current location, and distractions prior to gameplay. Results: Twenty-six cognitively-unimpaired older adults participated (mean age ± SD = 71.9 ± 8.6; 73% female). Gameplay time remained stable throughout the 4-months, with an average compliance rate of 91% ± 11% (1946 days of data across all participants) and weekly average playtime of 210 ± 132 min per participant. We observed an initial learning curve of improving game performance which on average, plateaued after 22-39 days, depending on the game. Higher levels of self-reported memory and thinking ability were associated with more gameplay time and sessions. Conclusion: MIND GamePack is a feasible and well-designed semi-passive cognitive assessment platform which may provide complementary data to traditional neuropsychological testing in research on aging and dementia.

Lateralization of Resting-State Networks in Children: Association with Age, Sex, Handedness, Intelligence Quotient, and Behavior.

Introduction: Lateralization in brain function has been associated with age and sex in previous work; however, there has been less focus on lateralization of functional networks during development. Aim: We aim to examine laterality in typical development; a clearer understanding of how and to what extent functional brain networks are lateralized in typical development may eventually prove to hold predictive information in psychopathology. Material and Methods: In this study, we examine the lateralization of resting-state networks assessed with a group-independent component analysis using resting-state functional magnetic resonance imaging from a large cohort consisting of 774 children, ages 6-10 years. This is an extension of our previous work on normal aging in adults, where we now assess whether there are similar patterns in children. Results: Unlike the results from our study of healthy aging in adults, which showed a decrease in laterality with increasing age, in this study we found both decreases and increases in lateralization in multiple networks with development. For example, auditory and sensorimotor regions had greater bilateral connectivity with development, whereas regions including the dorsolateral frontal cortex (Brodmann area left 9 and left 46) showed an increase in left lateralization with development. Conclusion: Our findings support a complex, nonlinear association between laterality and age in school-age children, a time when brain function and structure are developing rapidly. We also found brain networks in which laterality was significantly associated with sex, handedness, and intelligence quotient, but we did not find any significant association with behavioral scores. Impact statement Lateralization in brain function has been associated with age and sex in several previous studies; however, there has been less focus on lateralization of functional networks during development. A clearer understanding of how and to what extent functional brain networks are lateralized in typical development may eventually prove to hold predictive information in psychopathology. In this study, we examine the lateralization of resting-state networks assessed with a group-independent component analysis using resting-state functional magnetic resonance imaging from a large cohort consisting of 774 children, ages 6-10 years.

A Classification-Based Approach to Estimate the Number of Resting Functional Magnetic Resonance Imaging Dynamic Functional Connectivity States.

Aim: To determine the optimal number of connectivity states in dynamic functional connectivity analysis. Introduction: Recent work has focused on the study of dynamic (vs. static) brain connectivity in resting functional magnetic resonance imaging data. In this work, we focus on temporal correlation between time courses extracted from coherent networks called functional network connectivity (FNC). Dynamic FNC is most commonly estimated using a sliding window-based approach to capture short periods of FNC change. These data are then clustered to estimate transient connectivity patterns or states. Determining the number of states is a challenging problem. The elbow criterion is one of the widely used approaches to determine the connectivity states. Materials and Methods: In our work, we present an alternative approach that evaluates classification (e.g., healthy controls [HCs] vs. patients) as a measure to select the optimal number of states (clusters). We apply different classification strategies to perform classification between HCs and patients with schizophrenia for different numbers of states (i.e., varying the model order in the clustering algorithm). We compute cross-validated accuracy for different model orders to evaluate the classification performance. Results: Our results are consistent with our earlier work which shows that overall accuracy improves when dynamic connectivity measures are used separately or in combination with static connectivity measures. Results also show that the optimal model order for classification is different from that using the standard k-means model selection method, and that such optimization improves cross-validated accuracy. The optimal model order obtained from the proposed approach also gives significantly improved classification performance over the traditional model selection method. Conclusion: The observed results suggest that if one's goal is to perform classification, using the proposed approach as a criterion for selecting the optimal number of states in dynamic connectivity analysis leads to improved accuracy in hold-out data.

Association between metabolic syndrome and resting-state functional brain connectivity.

The objective of this study is to examine whether metabolic syndrome (MetS), the clustering of 3 or more cardiovascular risk factors, disrupts the resting-state functional connectivity (FC) of the large-scale cortical brain networks. Resting-state functional magnetic resonance imaging data were collected from seventy-eight middle-aged and older adults living with and without MetS (27 MetS; 51 non-MetS). FC maps were derived from the time series of intrinsic activity in the large-scale brain networks by correlating the spatially averaged time series with all brain voxels using a whole-brain seed-based FC approach. Participants with MetS showed hyperconnectivity across the core brain regions with evidence of loss of modularity when compared with non-MetS individuals. Furthermore, patterns of higher between-network MetS-related effects were observed across most of the seed regions in both right and left hemispheres. These findings indicate that MetS is associated with altered intrinsic communication across core neural networks and disrupted between-network connections across the brain due to the co-occurring vascular risk factors in MetS.

Transient Patterns of Functional Dysconnectivity in Clinical High Risk and Early Illness Schizophrenia Individuals Compared with Healthy Controls.

Schizophrenia shows abnormal dynamic functional network connectivity (dFNC), but it is unclear whether these abnormalities are present early in the illness course or precede illness onset in individuals at clinical high risk (CHR) for psychosis. We examined dFNC from resting-state functional magnetic resonance imaging data in CHR (n = 53), early illness schizophrenia (ESZ; n = 58), and healthy control (HC; n = 70) individuals. We applied a sliding temporal window approach capturing five distinct dFNC states. In ESZ patients, the likelihood of transitioning from state 4, a state that exhibited greater cortical-subcortical hyperconnectivity and also lacked typically observed anticorrelation between the default mode network and other functional networks, to a hypoconnected state was increased compared with HC and CHR groups. Furthermore, we investigated the interaction of group and state on dFNC. Overall, HC individuals showed significant changes of connectivity between states that were absent or altered in ESZ patients and CHR individuals. Connectivity differences between groups were identified primarily in two out of the five states, in particular, between HC and ESZ groups. In summary, it appears that the interaction effect was mostly driven by (1) dynamic connectivity changes in HC that were abnormal in CHR and ESZ individuals and (2) the fact that dysconnectivity between groups was only present in some states. These findings underscore the likelihood that abnormalities are present not only in static FNC but also in dFNC, in individuals at CHR for schizophrenia.

Aberrant patterns of default-mode network functional connectivity associated with metabolic syndrome: A resting-state study.

INTRODUCTION: Metabolic syndrome (MetS) is a clustering of three or more cardiovascular risk factors (RF), including hypertension, obesity, high cholesterol, or hyperglycemia. MetS and its component RFs are more prevalent in older age, and can be accompanied by alterations in brain structure. Studies have shown altered functional connectivity (FC) in samples with individual RFs as well as in clinical populations that are at higher risk to develop MetS. These studies have indicated that the default mode network (DMN) may be particularly vulnerable, yet little is known about the overall impact of MetS on FC in this network. METHODS: In this study, we evaluated the integrity of FC to the DMN in participants with MetS relative to non-MetS individuals. Using a seed-based connectivity analysis approach, resting-state functional MRI (fMRI) data were analyzed, and the FC measures among the DMN seed (isthmus of the cingulate) and rest of the brain voxels were estimated. RESULTS: Participants with MetS demonstrated reduced positive connectivity between the DMN seed and left superior frontal regions, and reduced negative connectivity between the DMN seed and left superior parietal, left postcentral, right precentral, right superior temporal and right superior parietal regions, after accounting for age- and sex-effects. CONCLUSIONS: Our results suggest that MetS is associated with alterations in FC between the DMN and other regions of the brain. Furthermore, these results indicate that the overall burden of vascular RFs associated with MetS may, in part, contribute to the pathophysiology underlying aberrant FC in the DMN.

A Closer Look into the Role of Protein Tau in the Identification of Promising Therapeutic Targets for Alzheimer's Disease.

One of the most commonly known chronic neurodegenerative disorders, Alzheimer's disease (AD), manifests the common type of dementia in 60⁻80% of cases. From a clinical standpoint, a patent cognitive decline and a severe change in personality, as caused by a loss of neurons, is usually evident in AD with about 50 million people affected in 2016. The disease progression in patients is distinguished by a gradual plummet in cognitive functions, eliciting symptoms such as memory loss, and eventually requiring full-time medical care. From a histopathological standpoint, the defining characteristics are intracellular aggregations of hyper-phosphorylated tau protein, known as neurofibrillary tangles (NFT), and depositions of amyloid ß-peptides (Aß) in the brain. The abnormal phosphorylation of tau protein is attributed to a wide gamut of neurological disorders known as tauopathies. In addition to the hyperphosphorylated tau lesions, neuroinflammatory processes could occur in a sustained manner through astro-glial activation, resulting in the disease progression. Recent findings have suggested a strong interplay between the mechanism of Tau phosphorylation, disruption of microtubules, and synaptic loss and pathology of AD. The mechanisms underlying these interactions along with their respective consequences in Tau pathology are still ill-defined. Thus, in this review: (1) we highlight the interplays existing between Tau pathology and AD; and (2) take a closer look into its role while identifying some promising therapeutic advances including state of the art imaging techniques.

Variability in Resting State Network and Functional Network Connectivity Associated With Schizophrenia Genetic Risk: A Pilot Study.

Imaging genetics posits a valuable strategy for elucidating genetic influences on brain abnormalities in psychiatric disorders. However, association analysis between 2D genetic data (subject × genetic variable) and 3D first-level functional magnetic resonance imaging (fMRI) data (subject × voxel × time) has been challenging given the asymmetry in data dimension. A summary feature needs to be derived for the imaging modality to compute inter-modality association at subject level. In this work, we propose to use variability in resting state networks (RSNs) and functional network connectivity (FNC) as potential features for purpose of association analysis. We conducted a pilot study to investigate the proposed features in a dataset of 171 healthy controls and 134 patients with schizophrenia (SZ). We computed variability in RSN and FNC in a group independent component analysis framework and tested three types of variability metrics, namely Euclidean distance, Pearson correlation and Kullback-Leibler (KL) divergence. Euclidean distance and Pearson correlation metrics more effectively discriminated controls from patients than KL divergence. The group differences observed with variability in RSN and FNC were highly consistent, indicating patients presenting increased deviation from the cohort-common pattern of RSN and FNC than controls. The variability in RSN and FNC showed significant associations with network global efficiency, the more the deviation, the lower the efficiency. Furthermore, the RSN and FNC variability were found to associate with individual SZ risk SNPs as well as cumulative polygenic risk score for SZ. Collectively the current findings provide preliminary evidence for variability in RSN and FNC being promising imaging features that may find applications as biomarkers and in imaging genetic association analysis.

Reduced higher-dimensional resting state fMRI dynamism in clinical high-risk individuals for schizophrenia identified by meta-state analysis.

New techniques to investigate functional network connectivity in resting state functional magnetic resonance imaging data have recently emerged. One novel approach, called meta-state analysis, goes beyond the mere cross-correlation of time courses of distinct brain areas and explores temporal dynamism in more detail, allowing for connectivity states to overlap in time and capturing global dynamic behavior. Previous studies have shown that patients with chronic schizophrenia exhibit reduced neural dynamism compared to healthy controls, but it is not known whether these alterations extend to earlier phases of the illness. In this study, we analyzed individuals at clinical high-risk (CHR, n = 53) for developing psychosis, patients in an early stage of schizophrenia (ESZ, n = 58), and healthy controls (HC, n = 70). ESZ individuals exhibit reduced neural dynamism across all domains compared to HC. CHR individuals also show reduced neural dynamism but only in 2 out of 4 domains investigated. Overall, meta-state analysis adds information about dynamic fluidity of functional connectivity.

Schizophrenia Shows Disrupted Links between Brain Volume and Dynamic Functional Connectivity.

Studies featuring multimodal neuroimaging data fusion for understanding brain function and structure, or disease characterization, leverage the partial information available in each of the modalities to reveal data variations not exhibited through the independent analyses. Similar to other complex syndromes, the characteristic brain abnormalities in schizophrenia may be better understood with the help of the additional information conveyed by leveraging an advanced modeling method involving multiple modalities. In this study, we propose a novel framework to fuse feature spaces corresponding to functional magnetic resonance imaging (functional) and gray matter (structural) data from 151 schizophrenia patients and 163 healthy controls. In particular, the features for the functional and structural modalities include dynamic (i.e., time-varying) functional network connectivity (dFNC) maps and the intensities of the gray matter (GM) maps, respectively. The dFNC maps are estimated from group independent component analysis (ICA) network time-courses by first computing windowed functional correlations using a sliding window approach, and then estimating subject specific states from this windowed data using temporal ICA followed by spatio-temporal regression. For each subject, the functional data features are horizontally concatenated with the corresponding GM features to form a combined feature space that is subsequently decomposed through a symmetric multimodal fusion approach involving a combination of multiset canonical correlation analysis (mCCA) and joint ICA (jICA). Our novel combined analyses successfully linked changes in the two modalities and revealed significantly disrupted links between GM volumes and time-varying functional connectivity in schizophrenia. Consistent with prior research, we found significant group differences in GM comprising regions in the superior parietal lobule, precuneus, postcentral gyrus, medial/superior frontal gyrus, superior/middle temporal gyrus, insula and fusiform gyrus, and several significant aberrations in the inter-regional functional connectivity strength as well. Importantly, structural and dFNC measures have independently shown changes associated with schizophrenia, and in this work we begin the process of evaluating the links between the two, which could shed light on the illness beyond what we can learn from a single imaging modality. In future work, we plan to evaluate replication of the inferred structure-function relationships in independent partitions of larger multi-modal schizophrenia datasets.

Regular cannabis and alcohol use is associated with resting-state time course power spectra in incarcerated adolescents.

Cannabis and alcohol are believed to have widespread effects on the brain. Although adolescents are at increased risk for substance use, the adolescent brain may also be particularly vulnerable to the effects of drug exposure due to its rapid maturation. Here, we examined the association between cannabis and alcohol use duration and resting-state functional connectivity in a large sample of male juvenile delinquents. The present sample was drawn from the Southwest Advanced Neuroimaging Cohort, Youth sample, and from a youth detention facility in Wisconsin. All participants were scanned at the maximum-security facilities using The Mind Research Network's 1.5T Avanto SQ Mobile MRI scanner. Information on cannabis and alcohol regular use duration was collected using self-report. Resting-state networks were computed using group independent component analysis in 201 participants. Associations with cannabis and alcohol use were assessed using Mancova analyses controlling for age, IQ, smoking and psychopathy scores in the complete case sample of 180 male juvenile delinquents. No associations between alcohol or cannabis use and network spatial maps were found. Longer cannabis use was associated with decreased low frequency power of the default mode network, the executive control networks (ECNs), and several sensory networks, and with decreased functional network connectivity. Duration of alcohol use was associated with decreased low frequency power of the right frontoparietal network, salience network, dorsal attention network, and several sensory networks. Our findings suggest that adolescent cannabis and alcohol use are associated with widespread differences in resting-state time course power spectra, which may persist even after abstinence.