Structural white matter abnormalities in Schizophrenia and associations with neurocognitive performance and symptom severity.

Schizophrenia is associated with robust white matter (WM) abnormalities but influences of potentially confounding variables and relationships with cognitive performance and symptom severity remain to be fully determined. This study was designed to evaluate WM abnormalities based on diffusion tensor imaging (DTI) in individuals with schizophrenia, and their relationships with cognitive performance and symptom severity. Data from individuals with schizophrenia (SZ; n=138, mean age±SD=39.02±11.82; 105 males) and healthy controls (HC; n=143, mean age±SD=37.07±10.84; 102 males) were collected as part of the Function Biomedical Informatics Research Network Phase 3 study. Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were compared between individuals with schizophrenia and healthy controls, and their relationships with neurocognitive performance and symptomatology assessed. Individuals with SZ had significantly lower FA in forceps minor and the left inferior fronto-occipital fasciculus compared to HC. FA in several tracts were associated with speed of processing and attention/vigilance and the severity of the negative symptom alogia. This study suggests that regional WM abnormalities are fundamentally involved in the pathophysiology of schizophrenia and may contribute to cognitive performance deficits and symptom expression observed in schizophrenia.

Hippocampal sclerosis and temporal lobe epilepsy following febrile status epilepticus: The FEBSTAT study.

OBJECTIVE: This study was undertaken to determine whether hippocampal T2 hyperintensity predicts sequelae of febrile status epilepticus, including hippocampal atrophy, sclerosis, and mesial temporal lobe epilepsy. METHODS: Acute magnetic resonance imaging (MRI) was obtained within a mean of 4.4 (SD = 5.5, median = 2.0) days after febrile status on >200 infants with follow-up MRI at approximately 1, 5, and 10 years. Hippocampal size, morphology, and T2 signal intensity were scored visually by neuroradiologists blinded to clinical details. Hippocampal volumetry provided quantitative measurement. Upon the occurrence of two or more unprovoked seizures, subjects were reassessed for epilepsy. Hippocampal volumes were normalized using total brain volumes. RESULTS: Fourteen of 22 subjects with acute hippocampal T2 hyperintensity returned for follow-up MRI, and 10 developed definite hippocampal sclerosis, which persisted through the 10-year follow-up. Hippocampi appearing normal initially remained normal on visual inspection. However, in subjects with normal-appearing hippocampi, volumetrics indicated that male, but not female, hippocampi were smaller than controls, but increasing hippocampal asymmetry was not seen following febrile status. Forty-four subjects developed epilepsy; six developed mesial temporal lobe epilepsy and, of the six, two had definite, two had equivocal, and two had no hippocampal sclerosis. Only one subject developed mesial temporal epilepsy without initial hyperintensity, and that subject had hippocampal malrotation. Ten-year cumulative incidence of all types of epilepsy, including mesial temporal epilepsy, was highest in subjects with initial T2 hyperintensity and lowest in those with normal signal and no other brain abnormalities. SIGNIFICANCE: Hippocampal T2 hyperintensity following febrile status epilepticus predicted hippocampal sclerosis and significant likelihood of mesial temporal lobe epilepsy. Normal hippocampal appearance in the acute postictal MRI was followed by maintained normal appearance, symmetric growth, and lower risk of epilepsy. Volumetric measurement detected mildly decreased hippocampal volume in males with febrile status.

Auditory oddball hypoactivation in schizophrenia.

Individuals with schizophrenia (SZ) show aberrant activations, assessed via functional magnetic resonance imaging (fMRI), during auditory oddball tasks. However, associations with cognitive performance and genetic contributions remain unknown. This study compares individuals with SZ to healthy volunteers (HVs) using two cross-sectional data sets from multi-center brain imaging studies. It examines brain activation to auditory oddball targets, and their associations with cognitive domain performance, schizophrenia polygenic risk scores (PRS), and genetic variation (loci). Both sample 1 (137 SZ vs. 147 HV) and sample 2 (91 SZ vs. 98 HV), showed hypoactivation in SZ in the left-frontal pole, and right frontal orbital, frontal pole, paracingulate, intracalcarine, precuneus, supramarginal and hippocampal cortices, and right thalamus. In SZ, precuneus activity was positively related to cognitive performance. Schizophrenia PRS showed a negative correlation with brain activity in the right-supramarginal cortex. GWA analyses revealed significant single-nucleotide polymorphisms associated with right-supramarginal gyrus activity. RPL36 also predicted right-supramarginal gyrus activity. In addition to replicating hypoactivation for oddball targets in SZ, this study identifies novel relationships between regional activity, cognitive performance, and genetic loci that warrant replication, emphasizing the need for continued data sharing and collaborative efforts.

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

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

Association of Heavy Drinking With Deviant Fiber Tract Development in Frontal Brain Systems in Adolescents.

Importance: Maturation of white matter fiber systems subserves cognitive, behavioral, emotional, and motor development during adolescence. Hazardous drinking during this active neurodevelopmental period may alter the trajectory of white matter microstructural development, potentially increasing risk for developing alcohol-related dysfunction and alcohol use disorder in adulthood. Objective: To identify disrupted adolescent microstructural brain development linked to drinking onset and to assess whether the disruption is more pronounced in younger rather than older adolescents. Design, Setting, and Participants: This case-control study, conducted from January 13, 2013, to January 15, 2019, consisted of an analysis of 451 participants from the National Consortium on Alcohol and Neurodevelopment in Adolescence cohort. Participants were aged 12 to 21 years at baseline and had at least 2 usable magnetic resonance diffusion tensor imaging (DTI) scans and up to 5 examination visits spanning 4 years. Participants with a youth-adjusted Cahalan score of 0 were labeled as no-to-low drinkers; those with a score of greater than 1 for at least 2 consecutive visits were labeled as heavy drinkers. Exploratory analysis was conducted between no-to-low and heavy drinkers. A between-group analysis was conducted between age- and sex-matched youths, and a within-participant analysis was performed before and after drinking. Exposures: Self-reported alcohol consumption in the past year summarized by categorical drinking levels. Main Outcomes and Measures: Diffusion tensor imaging measurement of fractional anisotropy (FA) in the whole brain and fiber systems quantifying the developmental change of each participant as a slope. Results: Analysis of whole-brain FA of 451 adolescents included 291 (64.5%) no-to-low drinkers and 160 (35.5%) heavy drinkers who indicated the potential for a deleterious association of alcohol with microstructural development. Among the no-to-low drinkers, 142 (48.4%) were boys with mean (SD) age of 16.5 (2.2) years and 149 (51.2%) were girls with mean (SD) age of 16.5 (2.1) years and 192 (66.0%) were White participants. Among the heavy drinkers, 86 (53.8%) were boys with mean (SD) age of 20.1 (1.5) years and 74 (46.3%) were girls with mean (SD) age of 20.5 (2.0) years and 142 (88.8%) were White participants. A group analysis revealed FA reduction in heavy-drinking youth compared with age- and sex-matched controls (t154 = -2.7, P = .008). The slope of this reduction correlated with log of days of drinking since the baseline visit (r156 = -0.21, 2-tailed P = .008). A within-participant analysis contrasting developmental trajectories of youths before and after they initiated heavy drinking supported the prediction that drinking onset was associated with and potentially preceded disrupted white matter integrity. Age-alcohol interactions (t152 = 3.0, P = .004) observed for the FA slopes indicated that the alcohol-associated disruption was greater in younger than older adolescents and was most pronounced in the genu and body of the corpus callosum, regions known to continue developing throughout adolescence. Conclusions and Relevance: This case-control study of adolescents found a deleterious association of alcohol use with white matter microstructural integrity. These findings support the concept of heightened vulnerability to environmental agents, including alcohol, associated with attenuated development of major white matter tracts in early adolescence.

Adolescent alcohol use disrupts functional neurodevelopment in sensation seeking girls.

Exogenous causes, such as alcohol use, and endogenous factors, such as temperament and sex, can modulate developmental trajectories of adolescent neurofunctional maturation. We examined how these factors affect sexual dimorphism in brain functional networks in youth drinking below diagnostic threshold for alcohol use disorder (AUD). Based on the 3-year, annually acquired, longitudinal resting-state functional magnetic resonance imaging (MRI) data of 526 adolescents (12-21 years at baseline) from the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) cohort, developmental trajectories of 23 intrinsic functional networks (IFNs) were analyzed for (1) sexual dimorphism in 259 participants who were no-to-low drinkers throughout this period; (2) sex-alcohol interactions in two age- and sex-matched NCANDA subgroups (N = 76 each), half no-to-low, and half moderate-to-heavy drinkers; and (3) moderating effects of gender-specific alcohol dose effects and a multifactorial impulsivity measure on IFN connectivity in all NCANDA participants. Results showed that sex differences in no-to-low drinkers diminished with age in the inferior-occipital network, yet girls had weaker within-network connectivity than boys in six other networks. Effects of adolescent alcohol use were more pronounced in girls than boys in three IFNs. In particular, girls showed greater within-network connectivity in two motor networks with more alcohol consumption, and these effects were mediated by sensation-seeking only in girls. Our results implied that drinking might attenuate the naturally diminishing sexual differences by disrupting the maturation of network efficiency more severely in girls. The sex-alcohol-dose effect might explain why women are at higher risk of alcohol-related health and psychosocial consequences than men.

Meta-Modal Information Flow: A Method for Capturing Multimodal Modular Disconnectivity in Schizophrenia.

OBJECTIVE: Multimodal measurements of the same phenomena provide complementary information and highlight different perspectives, albeit each with their own limitations. A focus on a single modality may lead to incorrect inferences, which is especially important when a studied phenomenon is a disease. In this paper, we introduce a method that takes advantage of multimodal data in addressing the hypotheses of disconnectivity and dysfunction within schizophrenia (SZ). METHODS: We start with estimating and visualizing links within and among extracted multimodal data features using a Gaussian graphical model (GGM). We then propose a modularity-based method that can be applied to the GGM to identify links that are associated with mental illness across a multimodal data set. Through simulation and real data, we show our approach reveals important information about disease-related network disruptions that are missed with a focus on a single modality. We use functional MRI (fMRI), diffusion MRI (dMRI), and structural MRI (sMRI) to compute the fractional amplitude of low frequency fluctuations (fALFF), fractional anisotropy (FA), and gray matter (GM) concentration maps. These three modalities are analyzed using our modularity method. RESULTS: Our results show missing links that are only captured by the cross-modal information that may play an important role in disconnectivity between the components. CONCLUSION: We identified multimodal (fALFF, FA and GM) disconnectivity in the default mode network area in patients with SZ, which would not have been detectable in a single modality. SIGNIFICANCE: The proposed approach provides an important new tool for capturing information that is distributed among multiple imaging modalities.

Dentate gyrus volume deficit in schizophrenia.

BACKGROUND: Schizophrenia is associated with robust hippocampal volume deficits but subregion volume deficits, their associations with cognition, and contributing genes remain to be determined. METHODS: Hippocampal formation (HF) subregion volumes were obtained using FreeSurfer 6.0 from individuals with schizophrenia (n = 176, mean age ± s.d. = 39.0 ± 11.5, 132 males) and healthy volunteers (n = 173, mean age ± s.d. = 37.6 ± 11.3, 123 males) with similar mean age, gender, handedness, and race distributions. Relationships between the HF subregion volume with the largest between group difference, neuropsychological performance, and single-nucleotide polymorphisms were assessed. RESULTS: This study found a significant group by region interaction on hippocampal subregion volumes. Compared to healthy volunteers, individuals with schizophrenia had significantly smaller dentate gyrus (DG) (Cohen's d = -0.57), Cornu Ammonis (CA) 4, molecular layer of the hippocampus, hippocampal tail, and CA 1 volumes, when statistically controlling for intracranial volume; DG (d = -0.43) and CA 4 volumes remained significantly smaller when statistically controlling for mean hippocampal volume. DG volume showed the largest between group difference and significant positive associations with visual memory and speed of processing in the overall sample. Genome-wide association analysis with DG volume as the quantitative phenotype identified rs56055643 (ß = 10.8, p < 5 × 10-8, 95% CI 7.0-14.5) on chromosome 3 in high linkage disequilibrium with MOBP. Gene-based analyses identified associations between SLC25A38 and RPSA and DG volume. CONCLUSIONS: This study suggests that DG dysfunction is fundamentally involved in schizophrenia pathophysiology, that it may contribute to cognitive abnormalities in schizophrenia, and that underlying biological mechanisms may involve contributions from MOBP, SLC25A38, and RPSA.

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

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

Autoconnectivity: A new perspective on human brain function.

BACKGROUND: Autocorrelation (AC) in fMRI time-series is a well-known phenomenon, typically attributed to colored noise and therefore removed from the data. We hypothesize that AC reflects systematic and meaningful signal fluctuations that may be tied to neural activity and provide evidence to support this hypothesis. NEW METHOD: Each fMRI time-series is modeled as an autoregressive process from which the autocorrelation is quantified. Then, autocorrelation during resting-state fMRI and auditory oddball (AOD) task in schizophrenia and healthy volunteers is examined. RESULTS: During resting-state, AC was higher in the visual cortex while during AOD task, frontal part of the brain exhibited higher AC in both groups. AC values were significantly lower in specific brain regions in schizophrenia patients (such as thalamus during resting-state) compared to healthy controls in two independent datasets. Moreover, AC values had significant negative correlation with patients' symptoms. AC differences discriminated patients from healthy controls with high accuracy (resting-state). COMPARISON WITH EXISTING METHODS: Contrary to most prior works, the results suggest AC shows meaningful patterns that are discriminative between patients and controls. Our results are in line with recent works attributing autocorrelation to feedback loop of brain's regulatory circuit. CONCLUSIONS: Autoconnectivity is cognitive state dependent (resting-state vs. task) and mental state dependent (healthy vs. schizophrenia). The concept of autoconnectivity resembles a recurrent neural network and provides a new perspective of functional integration in the brain. These findings may have important implications for understanding of brain function in health and disease as well as for analysis of fMRI time-series.

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.

Distribution of brain iron accrual in adolescence: Evidence from cross-sectional and longitudinal analysis.

To track iron accumulation and location in the brain across adolescence, we repurposed diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) data acquired in 513 adolescents and validated iron estimates with quantitative susceptibility mapping (QSM) in 104 of these subjects. DTI and fMRI data were acquired longitudinally over 1 year in 245 male and 268 female, no-to-low alcohol-consuming adolescents (12-21 years at baseline) from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study. Brain region average signal values were calculated for susceptibility to nonheme iron deposition: pallidum, putamen, dentate nucleus, red nucleus, and substantia nigra. To estimate nonheme iron, the corpus callosum signal (robust to iron effects) was divided by regional signals to generate estimated R2 (edwR2 for DTI) and R2 * (eR2 * for fMRI). Longitudinal iron deposition was measured using the normalized signal change across time for each subject. Validation using baseline QSM, derived from susceptibility-weighted imaging, was performed on 46 male and 58 female participants. Normalized iron deposition estimates from DTI and fMRI correlated with age in most regions; both estimates indicated less iron in boys than girls. QSM results correlated highly with DTI and fMRI results (adjusted R2 = 0.643 for DTI, 0.578 for fMRI). Cross-sectional and longitudinal analyses indicated an initial rapid increase in iron, notably in the putamen and red nucleus, that slowed with age. DTI and fMRI data can be repurposed for identifying regional brain iron deposition in developing adolescents as validated with high correspondence with QSM.

Multimodal neuromarkers in schizophrenia via cognition-guided MRI fusion.

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.

Polygenic risk score, genome-wide association, and gene set analyses of cognitive domain deficits in schizophrenia.

This study assessed genetic contributions to six cognitive domains, identified by the MATRICS Cognitive Consensus Battery as relevant for schizophrenia, cognition-enhancing, clinical trials. Psychiatric Genomics Consortium Schizophrenia polygenic risk scores showed significant negative correlations with each cognitive domain. Genome-wide association analyses identified loci associated with attention/vigilance (rs830786 within HNF4G), verbal memory (rs67017972 near NDUFS4), and reasoning/problem solving (rs76872642 within HDAC9). Gene set analysis identified unique and shared genes across cognitive domains. These findings suggest involvement of common and unique mechanisms across cognitive domains and may contribute to the discovery of new therapeutic targets to treat cognitive deficits in schizophrenia.

Influences of Age, Sex, and Moderate Alcohol Drinking on the Intrinsic Functional Architecture of Adolescent Brains.

The transition from adolescent to adult cognition and emotional control requires neurodevelopmental maturation likely involving intrinsic functional networks (IFNs). Normal neurodevelopment may be vulnerable to disruption from environmental insult such as alcohol consumption commonly initiated during adolescence. To test potential disruption to IFN maturation, we used resting-state functional magnetic resonance imaging (rs-fMRI) in 581 no-to-low alcohol-consuming and 117 moderate-to-high-drinking youth. Functional seed-to-voxel connectivity analysis assessed age, sex, and moderate alcohol drinking on default-mode, executive-control, salience, reward, and emotion networks and tested cognitive and motor coordination correlates of network connectivity. Among no-to-low alcohol-consuming adolescents, executive-control frontolimbicstriatal connectivity was stronger in older than younger adolescents, particularly boys, and predicted better ability in balance, memory, and impulse control. Connectivity patterns in moderate-to-high-drinking youth were tested mainly in late adolescence when drinking was initiated. Implicated was the emotion network with attenuated connectivity to default-mode network regions. Our cross-sectional rs-fMRI findings from this large cohort of adolescents show sexual dimorphism in connectivity and suggest neurodevelopmental rewiring toward stronger and spatially more distributed executive-control networking in older than younger adolescents. Functional network rewiring in moderate-to-high-drinking adolescents may impede maturation of affective and self-reflection systems and obscure maturation of complex social and emotional behaviors.

Multimodal Fusion With Reference: Searching for Joint Neuromarkers of Working Memory Deficits in Schizophrenia.

By exploiting cross-information among multiple imaging data, multimodal fusion has often been used to better understand brain diseases. However, most current fusion approaches are blind, without adopting any prior information. There is increasing interest to uncover the neurocognitive mapping of specific clinical measurements on enriched brain imaging data; hence, a supervised, goal-directed model that employs prior information as a reference to guide multimodal data fusion is much needed and becomes a natural option. Here, we proposed a fusion with reference model called "multi-site canonical correlation analysis with reference + joint-independent component analysis" (MCCAR+jICA), which can precisely identify co-varying multimodal imaging patterns closely related to the reference, such as cognitive scores. In a three-way fusion simulation, the proposed method was compared with its alternatives on multiple facets; MCCAR+jICA outperforms others with higher estimation precision and high accuracy on identifying a target component with the right correspondence. In human imaging data, working memory performance was utilized as a reference to investigate the co-varying working memory-associated brain patterns among three modalities and how they are impaired in schizophrenia. Two independent cohorts (294 and 83 subjects respectively) were used. Similar brain maps were identified between the two cohorts along with substantial overlaps in the central executive network in fMRI, salience network in sMRI, and major white matter tracts in dMRI. These regions have been linked with working memory deficits in schizophrenia in multiple reports and MCCAR+jICA further verified them in a repeatable, joint manner, demonstrating the ability of the proposed method to identify potential neuromarkers for mental disorders.

Harmonizing DTI measurements across scanners to examine the development of white matter microstructure in 803 adolescents of the NCANDA study.

Neurodevelopment continues through adolescence, with notable maturation of white matter tracts comprising regional fiber systems progressing at different rates. To identify factors that could contribute to regional differences in white matter microstructure development, large samples of youth spanning adolescence to young adulthood are essential to parse these factors. Recruitment of adequate samples generally relies on multi-site consortia but comes with the challenge of merging data acquired on different platforms. In the current study, diffusion tensor imaging (DTI) data were acquired on GE and Siemens systems through the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA), a multi-site study designed to track the trajectories of regional brain development during a time of high risk for initiating alcohol consumption. This cross-sectional analysis reports baseline Tract-Based Spatial Statistic (TBSS) of regional fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (L1), and radial diffusivity (LT) from the five consortium sites on 671 adolescents who met no/low alcohol or drug consumption criteria and 132 adolescents with a history of exceeding consumption criteria. Harmonization of DTI metrics across manufacturers entailed the use of human-phantom data, acquired multiple times on each of three non-NCANDA participants at each site's MR system, to determine a manufacturer-specific correction factor. Application of the correction factor derived from human phantom data measured on MR systems from different manufacturers reduced the standard deviation of the DTI metrics for FA by almost a half, enabling harmonization of data that would have otherwise carried systematic error. Permutation testing supported the hypothesis of higher FA and lower diffusivity measures in older adolescents and indicated that, overall, the FA, MD, and L1 of the boys were higher than those of the girls, suggesting continued microstructural development notable in the boys. The contribution of demographic and clinical differences to DTI metrics was assessed with General Additive Models (GAM) testing for age, sex, and ethnicity differences in regional skeleton mean values. The results supported the primary study hypothesis that FA skeleton mean values in the no/low-drinking group were highest at different ages. When differences in intracranial volume were covaried, FA skeleton mean reached a maximum at younger ages in girls than boys and varied in magnitude with ethnicity. Our results, however, did not support the hypothesis that youth who exceeded exposure criteria would have lower FA or higher diffusivity measures than the no/low-drinking group; detecting the effects of excessive alcohol consumption during adolescence on DTI metrics may require longitudinal study.

The Function Biomedical Informatics Research Network Data Repository.

The Function Biomedical Informatics Research Network (FBIRN) developed methods and tools for conducting multi-scanner functional magnetic resonance imaging (fMRI) studies. Method and tool development were based on two major goals: 1) to assess the major sources of variation in fMRI studies conducted across scanners, including instrumentation, acquisition protocols, challenge tasks, and analysis methods, and 2) to provide a distributed network infrastructure and an associated federated database to host and query large, multi-site, fMRI and clinical data sets. In the process of achieving these goals the FBIRN test bed generated several multi-scanner brain imaging data sets to be shared with the wider scientific community via the BIRN Data Repository (BDR). The FBIRN Phase 1 data set consists of a traveling subject study of 5 healthy subjects, each scanned on 10 different 1.5 to 4 T scanners. The FBIRN Phase 2 and Phase 3 data sets consist of subjects with schizophrenia or schizoaffective disorder along with healthy comparison subjects scanned at multiple sites. In this paper, we provide concise descriptions of FBIRN's multi-scanner brain imaging data sets and details about the BIRN Data Repository instance of the Human Imaging Database (HID) used to publicly share the data.

Adolescent Development of Cortical and White Matter Structure in the NCANDA Sample: Role of Sex, Ethnicity, Puberty, and Alcohol Drinking.

Brain structural development continues throughout adolescence, when experimentation with alcohol is often initiated. To parse contributions from biological and environmental factors on neurodevelopment, this study used baseline National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) magnetic resonance imaging (MRI) data, acquired in 674 adolescents meeting no/low alcohol or drug use criteria and 134 adolescents exceeding criteria. Spatial integrity of images across the 5 recruitment sites was assured by morphological scaling using Alzheimer's disease neuroimaging initiative phantom-derived volume scalar metrics. Clinical MRI readings identified structural anomalies in 11.4%. Cortical volume and thickness were smaller and white matter volumes were larger in older than in younger adolescents. Effects of sex (male > female) and ethnicity (majority > minority) were significant for volume and surface but minimal for cortical thickness. Adjusting volume and area for supratentorial volume attenuated or removed sex and ethnicity effects. That cortical thickness showed age-related decline and was unrelated to supratentorial volume is consistent with the radial unit hypothesis, suggesting a universal neural development characteristic robust to sex and ethnicity. Comparison of NCANDA with PING data revealed similar but flatter, age-related declines in cortical volumes and thickness. Smaller, thinner frontal, and temporal cortices in the exceeds-criteria than no/low-drinking group suggested untoward effects of excessive alcohol consumption on brain structural development.

Supervised multimodal fusion and its application in searching joint neuromarkers of working memory deficits in schizophrenia.

Multimodal fusion is an effective approach to better understand brain disease. To date, most current fusion approaches are unsupervised; there is need for a multivariate method that can adopt prior information to guide multimodal fusion. Here we proposed a novel supervised fusion model, called "MCCAR+jICA", which enables both identification of multimodal co-alterations and linking the covarying brain regions with a specific reference signal, e.g., cognitive scores. The proposed method has been validated on both simulated and real human brain data. Features from 3 modalities (fMRI, sMRI, dMRI) obtained from 147 schizophrenia patients and 147 age-matched healthy controls were included as fusion input, who participated in the Function Biomedical Informatics Research Network (FBIRN) Phase III study. Our aim was to investigate the group co-alterations seen in three types of MRI data that are also correlated with working memory performance. One joint IC was found both significantly group-discriminating (p=7.4E-06, 0.001, 7.0E-09) and highly correlated with working memory scores(r=0.296, 0.241, 0.301) and PANSS negative scores (r=-0.229, -0.276, -0.240) for fMRI, dMRI and sMRI, respectively. Given the simulation and FBIRN results, MCCAR+jICA is shown to be an effective multivariate approach to extract accurate and stable multimodal components associated with a particular measure of interest, and promises a wide application in identifying potential neuromarkers for mental disorders.