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1.  Evaluation of prostate segmentation algorithms for MRI: the PROMISE12 challenge 
Medical image analysis  2013;18(2):359-373.
Prostate MRI image segmentation has been an area of intense research due to the increased use of MRI as a modality for the clinical workup of prostate cancer. Segmentation is useful for various tasks, e.g. to accurately localize prostate boundaries for radiotherapy or to initialize multi-modal registration algorithms. In the past, it has been difficult for research groups to evaluate prostate segmentation algorithms on multi-center, multi-vendor and multi-protocol data. Especially because we are dealing with MR images, image appearance, resolution and the presence of artifacts are affected by differences in scanners and/or protocols, which in turn can have a large influence on algorithm accuracy. The Prostate MR Image Segmentation (PROMISE12) challenge was setup to allow a fair and meaningful comparison of segmentation methods on the basis of performance and robustness. In this work we will discuss the initial results of the online PROMISE12 challenge, and the results obtained in the live challenge workshop hosted by the MICCAI2012 conference. In the challenge, 100 prostate MR cases from 4 different centers were included, with differences in scanner manufacturer, field strength and protocol. A total of 11 teams from academic research groups and industry participated. Algorithms showed a wide variety in methods and implementation, including active appearance models, atlas registration and level sets. Evaluation was performed using boundary and volume based metrics which were combined into a single score relating the metrics to human expert performance. The winners of the challenge where the algorithms by teams Imorphics and ScrAutoProstate, with scores of 85.72 and 84.29 overall. Both algorithms where significantly better than all other algorithms in the challenge (p < 0.05) and had an efficient implementation with a run time of 8 minutes and 3 second per case respectively. Overall, active appearance model based approaches seemed to outperform other approaches like multi-atlas registration, both on accuracy and computation time. Although average algorithm performance was good to excellent and the Imorphics algorithm outperformed the second observer on average, we showed that algorithm combination might lead to further improvement, indicating that optimal performance for prostate segmentation is not yet obtained. All results are available online at http://promise12.grand-challenge.org/.
doi:10.1016/j.media.2013.12.002
PMCID: PMC4137968  PMID: 24418598
segmentation; prostate; MRI; challenge
2.  ODVBA-C: Optimally-Discriminative Voxel-Based Analysis of Continuous Variables 
In this paper, we propose a new method that utilizes a novel spatially adaptive scheme for detection of multivariate neuroimaging patterns relating to a continuous subject-level variable, aiming to effectively determine the optimal spatially adaptive filtering of neuroimaging data from the persepective of finding relationships between imaging and continues (e.g. clinical and cognitive) variables. Analyses employ local pattern analysis using regularized least square regression with nonnegativity constraints within a spatial neighborhood around each voxel. Within each neighborhood, we determine the optimal regression coefficients that relate local patterns to the continuous variable of interest. As each voxel belongs to multiple overlapping neighborhoods, the statistic for a given voxel is determined by combining weights from all neighborhoods to which the voxel participates. Finally, nonparametric permutation testing is used to obtain a voxelwise significance map. Using both simulated and real fMRI data, we demonstrate the effectiveness of the proposed method.
doi:10.1109/PRNI.2013.49
PMCID: PMC4259270  PMID: 25505793
fMRI; Regression; Nonnegativity; ODVBA
3.  Heterogeneous Impact of Motion on Fundamental Patterns of Developmental Changes in Functional Connectivity During Youth 
NeuroImage  2013;83:10.1016/j.neuroimage.2013.06.045.
Several independent studies have demonstrated that small amounts of in-scanner motion systematically bias estimates of resting-state functional connectivity. This confound is of particular importance for studies of neurodevelopment in youth because motion is strongly related to subject age during this period. Critically, the effects of motion on connectivity mimic major findings in neurodevelopmental research, specifically an age-related strengthening of distant connections and weakening of short-range connections. Here, in a sample of 780 subjects ages 8–22, we re-evaluate patterns of change in functional connectivity during adolescent development after rigorously controlling for the confounding influences of motion at both the subject and group level. We find that motion artifact inflates both overall estimates of age-related change as well as specific distance-related changes in connectivity. When motion is more fully accounted for, the prevalence of age-related change as well as the strength of distance-related effects is substantially reduced. However, age-related changes remain highly significant. In contrast, motion artifact tends to obscure age-related changes in connectivity associated with segregation of functional brain modules; improved preprocessing techniques allow greater sensitivity to detect increased within-module connectivity occurring with development. Finally, we show that subject’s age can still be accurately estimated from the multivariate pattern of functional connectivity even while controlling for motion. Taken together, these results indicate that while motion artifact has a marked and heterogeneous impact on estimates of connectivity change during adolescence, functional connectivity remains a valuable phenotype for the study of neurodevelopment.
doi:10.1016/j.neuroimage.2013.06.045
PMCID: PMC3874413  PMID: 23792981
motion artifact; fMRI; connectivity; development; adolescence; network; connectome; resting-state
4.  Multi-Atlas Skull-Stripping 
Academic radiology  2013;20(12):10.1016/j.acra.2013.09.010.
Rationale and Objectives
We present a new method for automatic brain extraction on structural magnetic resonance images, based on a multi-atlas registration framework.
Materials and Methods
Our method addresses fundamental challenges of multi-atlas approaches. To overcome the difficulties arising from the variability of imaging characteristics between studies, we propose a study-specific template selection strategy, by which we select a set of templates that best represent the anatomical variations within the data set. Against the difficulties of registering brain images with skull, we use a particularly adapted registration algorithm that is more robust to large variations between images, as it adaptively aligns different regions of the two images based not only on their similarity but also on the reliability of the matching between images. Finally, a spatially adaptive weighted voting strategy, which uses the ranking of Jacobian determinant values to measure the local similarity between the template and the target images, is applied for combining coregistered template masks.
Results
The method is validated on three different public data sets and obtained a higher accuracy than recent state-of-the-art brain extraction methods. Also, the proposed method is successfully applied on several recent imaging studies, each containing thousands of magnetic resonance images, thus reducing the manual correction time significantly.
Conclusions
The new method, available as a stand-alone software package for public use, provides a robust and accurate brain extraction tool applicable for both clinical use and large population studies.
doi:10.1016/j.acra.2013.09.010
PMCID: PMC3880117  PMID: 24200484
Brain extraction; registration; multi-atlas; label fusion; Jacobian determinant
5.  Memory decline shows stronger associations with estimated spatial patterns of amyloid deposition progression than total amyloid burden 
Neurobiology of aging  2013;34(12):2835-2842.
The development of amyloid imaging compounds has allowed in vivo imaging of amyloid deposition. In this study, we examine the spatial patterns of amyloid deposition throughout the brain using Pittsburgh Compound Blue (11C-PiB) PET data from the Baltimore Longitudinal Study of Aging. We used a new methodology that allows us to approximate spatial patterns of the temporal progression of amyloid plaque deposition from cross-sectional data. Our results are consistent with patterns of progression known from autopsy studies, with frontal and precuneus regions affected early and occipital and sensorimotor cortices affected later in disease progression – here, disease progression means lower-to-higher total amyloid burden. Furthermore, we divided participants into subgroups based on longitudinal change in memory performance and demonstrated significantly different spatial patterns of the estimated progression of amyloid deposition between these subgroups. Our results indicate that the spatial pattern of amyloid deposition is related to cognitive performance and may be more informative than a biomarker reflecting total amyloid burden, which is the current practice. This finding has broad implications for our understanding of the relationship between cognitive decline/resilience and amyloid deposition, as well as for the use of amyloid imaging as a biomarker in research and clinical applications.
doi:10.1016/j.neurobiolaging.2013.05.030
PMCID: PMC3893024  PMID: 23859610
Amyloid; PiB; PET; CVLT; cognition
6.  The Five Factors of personality and regional cortical variability in the Baltimore Longitudinal Study of Aging 
Human brain mapping  2012;34(11):10.1002/hbm.22108.
Although personality changes have been associated with brain lesions and atrophy caused by neurodegenerative diseases and aging, neuroanatomical correlates of personality in healthy individuals and their stability over time have received relatively little investigation. In this study, we explored regional gray matter (GM) volumetric associations of the five-factor model of personality. Eighty-seven healthy older adults took the NEO Personality Inventory and had brain MRI at two time points 2 years apart. We performed GM segmentation followed by regional analysis of volumes examined in normalized space map creation and voxel based morphometry-type statistical inference in SPM8. We created a regression model including all five factors and important covariates. Next, a conjunction analysis identified associations between personality scores and GM volumes that were replicable across time, also using cluster-level Family-Wise-Error correction. Larger right orbitofrontal and dorsolateral prefrontal cortices and rolandic operculum were associated with lower Neuroticism; larger left temporal, dorsolateral prefrontal, and anterior cingulate cortices with higher Extraversion; larger right frontopolar and smaller orbitofrontal and insular cortices with higher Openness; larger right orbitofrontal cortex with higher Agreeableness; larger dorsolateral prefrontal and smaller frontopolar cortices with higher Conscientiousness. In summary, distinct personality traits were associated with stable individual differences in GM volumes. As expected for higher-order traits, regions performing a large number of cognitive and affective functions were implicated. Our findings highlight personality-related variation that may be related to individual differences in brain structure that merit additional attention in neuroimaging research.
doi:10.1002/hbm.22108
PMCID: PMC3808519  PMID: 22610513
individual differences; trait; Neuroticism; Extraversion; Openness; Agreeableness; Conscientiousness; anterior cingulate; orbitofrontal cortex; frontopolar cortex
7.  Computer-aided Assessment of Regional Abdominal Fat with Food Residue Removal in CT 
Academic radiology  2013;20(11):1413-1421.
Rationale and Objectives
Separate quantification of abdominal subcutaneous and visceral fat regions is essential to understand the role of regional adiposity as risk factor in epidemiological studies. Fat quantification is often based on computed tomography (CT) because fat density is distinct from other tissue densities in the abdomen. However, the presence of intestinal food residues with densities similar to fat may reduce fat quantification accuracy. We introduce an abdominal fat quantification method in CT with interest in food residue removal.
Materials and Methods
Total fat was identified in the feature space of Hounsfield units and divided into subcutaneous and visceral components using model-based segmentation. Regions of food residues were identified and removed from visceral fat using a machine learning method integrating intensity, texture, and spatial information. Cost-weighting and bagging techniques were investigated to address class imbalance.
Results
We validated our automated food residue removal technique against semimanual quantifications. Our feature selection experiments indicated that joint intensity and texture features produce the highest classification accuracy at 95%. We explored generalization capability using k-fold cross-validation and receiver operating characteristic (ROC) analysis with variable k. Losses in accuracy and area under ROC curve between maximum and minimum k were limited to 0.1% and 0.3%. We validated tissue segmentation against reference semimanual delineations. The Dice similarity scores were as high as 93.1 for subcutaneous fat and 85.6 for visceral fat.
Conclusions
Computer-aided regional abdominal fat quantification is a reliable computational tool for large-scale epidemiological studies. Our proposed intestinal food residue reduction scheme is an original contribution of this work. Validation experiments indicate very good accuracy and generalization capability.
doi:10.1016/j.acra.2013.08.007
PMCID: PMC3954576  PMID: 24119354
Body composition assessment; false positive reduction
8.  Pattern Analysis of Dynamic Susceptibility Contrast MRI Reveals Peritumoral Tissue Heterogeneity 
Radiology  2014;273(2):502-510.
Purpose
The aim of this study is to augment the analysis of dynamic susceptibility contrast MRI (DSC-MRI) to uncover unique tissue characteristics that could potentially facilitate treatment planning through a better understanding of the peritumoral region of patients with glioblastoma.
Materials and Methods
IRB approval was obtained for this study with waiver of informed consent for retrospective review of medical records. DSC-MRI data was obtained for 79 patients and principal component analysis (PCA) was applied to the perfusion signal. The first six principal components (PCs) were sufficient to characterize more than 99% of variance in the temporal dynamics of blood perfusion in all regions of interest. The PCs were subsequently used in conjunction with a support vector machine (SVM) classifier to create a map of heterogeneity within the peritumoral region and the variance of this map served as the heterogeneity score.
Results
The calculated PCs allowed near perfect separability of tissue that was likely highly infiltrated from tissue that was unlikely infiltrated with tumor. The heterogeneity map created using the PCs showed a clear relationship between voxels judged by the SVM to be highly infiltrated and subsequent recurrence. The results demonstrated a significant correlation (r=0.46, p<0.0001) between the heterogeneity score and patient survival. The hazard ratio was 2.23 (95% CI, 1.4-3.6, p <0.01) between high and low heterogeneity score patients based on the median heterogeneity score.
Conclusion
Analysis of DSC-MRI data using PCA can identify imaging variables that can be subsequently utilized to evaluate the peritumoral region in glioblastoma. These variables are potentially indicative of tumor infiltration and may become useful tools in guiding therapy as well as individualized prognostication.
doi:10.1148/radiol.14132458
PMCID: PMC4208985  PMID: 24955928
Perfusion; Glioblastoma; DSC-MRI; PCA
9.  Combining Generative Models for Multifocal Glioma Segmentation and Registration 
In this paper, we propose a new method for simultaneously segmenting brain scans of glioma patients and registering these scans to a normal atlas. Performing joint segmentation and registration for brain tumors is very challenging when tumors include multifocal masses and have complex shapes with heterogeneous textures. Our approach grows tumors for each mass from multiple seed points using a tumor growth model and modifies a normal atlas into one with tumors and edema using the combined results of grown tumors. We also generate a tumor shape prior via the random walk with restart, utilizing multiple tumor seeds as initial foreground information. We then incorporate this shape prior into an EM framework which estimates the mapping between the modified atlas and the scans, posteriors for each tissue labels, and the tumor growth model parameters. We apply our method to the BRATS 2013 leaderboard dataset to evaluate segmentation performance. Our method shows the best performance among all participants.
PMCID: PMC4205485  PMID: 25333188
10.  Deriving statistical significance maps for support vector regression using medical imaging data 
Regression analysis involves predicting a continuous variable using imaging data. The Support Vector Regression (SVR) algorithm has previously been used in addressing regression analysis in neuroimaging. However, identifying the regions of the image that the SVR uses to model the dependence of a target variable remains an open problem. It is an important issue when one wants to biologically interpret the meaning of a pattern that predicts the variable(s) of interest, and therefore to understand normal or pathological process. One possible approach to the identification of these regions is the use of permutation testing. Permutation testing involves 1) generation of a large set of ‘null SVR models’ using randomly permuted sets of target variables, and 2) comparison of the SVR model trained using the original labels to the set of null models. These permutation tests often require prohibitively long computational time. Recent work in support vector classification shows that it is possible to analytically approximate the results of permutation testing in medical image analysis. We propose an analogous approach to approximate permutation testing based analysis for support vector regression with medical imaging data. In this paper we present 1) the theory behind our approximation, and 2) experimental results using two real datasets.
doi:10.1109/PRNI.2013.13
PMCID: PMC4199337  PMID: 25328907
Permutation testing; Support Vector Regression
11.  Multimodal Magnetic Resonance Imaging Study of Treatment-Naïve Adults with Attention-Deficit/Hyperactivity Disorder 
PLoS ONE  2014;9(10):e110199.
Background
Attention-Deficit/Hiperactivity Disorder (ADHD) is a prevalent disorder, but its neuroanatomical circuitry is still relatively understudied, especially in the adult population. The few morphometric magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) studies available to date have found heterogeneous results. This may be at least partly attributable to some well-known technical limitations of the conventional voxel-based methods usually employed to analyze such neuroimaging data. Moreover, there is a great paucity of imaging studies of adult ADHD to date that have excluded patients with history of use of stimulant medication.
Methods
A newly validated method named optimally-discriminative voxel-based analysis (ODVBA) was applied to multimodal (structural and DTI) MRI data acquired from 22 treatment-naïve ADHD adults and 19 age- and gender-matched healthy controls (HC).
Results
Regarding DTI data, we found higher fractional anisotropy in ADHD relative to HC encompassing the white matter (WM) of the bilateral superior frontal gyrus, right middle frontal left gyrus, left postcentral gyrus, bilateral cingulate gyrus, bilateral middle temporal gyrus and right superior temporal gyrus; reductions in trace (a measure of diffusivity) in ADHD relative to HC were also found in fronto-striatal-parieto-occipital circuits, including the right superior frontal gyrus and bilateral middle frontal gyrus, right precentral gyrus, left middle occipital gyrus and bilateral cingulate gyrus, as well as the left body and right splenium of the corpus callosum, right superior corona radiata, and right superior longitudinal and fronto-occipital fasciculi. Volumetric abnormalities in ADHD subjects were found only at a trend level of significance, including reduced gray matter (GM) in the right angular gyrus, and increased GM in the right supplementary motor area and superior frontal gyrus.
Conclusions
Our results suggest that adult ADHD is associated with neuroanatomical abnormalities mainly affecting the WM microstructure in fronto-parieto-temporal circuits that have been implicated in cognitive, emotional and visuomotor processes.
doi:10.1371/journal.pone.0110199
PMCID: PMC4195718  PMID: 25310815
12.  Optimally-Discriminative Voxel-Based Morphometry significantly increases the ability to detect group differences in Schizophrenia, Mild Cognitive Impairment, and Alzheimer’s Disease 
NeuroImage  2013;79:94-110.
Optimally-Discriminative Voxel-Based Analysis (ODVBA) (Zhang and Davatzikos, 2011) is a recently-developed and validated framework of voxel-based group analysis, which transcends limitations of traditional Gaussian smoothing in forms of analysis such as the General Linear Model (GLM). ODVBA estimates the optimal non-stationary and anisotropic filtering of the data prior to statistical analyses to maximize the ability to detect group differences. In this paper, we extensively evaluate ODVBA to three sets of previously published data from studies in schizophrenia, mild cognitive impairment, and Alzheimer’s disease, and evaluate the regions of structural difference identified by ODVBA versus standard Gaussian smoothing and other related methods. The experimental results suggest that ODVBA is considerably more sensitive in detecting group differences, presumably because of its ability to adapt the regional filtering to the underlying extent and shape of a group difference, thereby maximizing the ability to detect such difference. Although there is no gold standard in these clinical studies, ODVBA demonstrated highest significance in group differences within the identified voxels. In terms of spatial extent of detected area, agreement of anatomical boundary, and classification, it performed better than other tested voxel-based methods and competitively with the cluster enhancing methods.
doi:10.1016/j.neuroimage.2013.04.063
PMCID: PMC3715724  PMID: 23631985
Voxel-Based Morphometry; General Linear Model; Schizophrenia; Mild Cognitive Impairment; Alzheimer’s Disease; ODVBA
13.  Analytic estimation of statistical significance maps for support vector machine based multi-variate image analysis and classification 
NeuroImage  2013;78:270-283.
Multivariate pattern analysis (MVPA) methods such as support vector machines (SVMs) have been increasingly applied to fMRI and sMRI analyses, enabling the detection of distinctive imaging patterns. However, identifying brain regions that significantly contribute to the classification/group separation requires computationally expensive permutation testing. In this paper we show that the results of SVM-permutation testing can be analytically approximated. This approximation leads to more than a thousand fold speed up of the permutation testing procedure, thereby rendering it feasible to perform such tests on standard computers. The speed up achieved makes SVM based group difference analysis competitive with standard univariate group difference analysis methods.
doi:10.1016/j.neuroimage.2013.03.066
PMCID: PMC3767485  PMID: 23583748
SVM; Statistical inference; Neuroimaging analysis
14.  Sparse dictionary learning of resting state fMRI networks 
Research in resting state fMRI (rsfMRI) has revealed the presence of stable, anti-correlated functional subnetworks in the brain. Task-positive networks are active during a cognitive process and are anti-correlated with task-negative networks, which are active during rest. In this paper, based on the assumption that the structure of the resting state functional brain connectivity is sparse, we utilize sparse dictionary modeling to identify distinct functional sub-networks. We propose two ways of formulating the sparse functional network learning problem that characterize the underlying functional connectivity from different perspectives. Our results show that the whole-brain functional connectivity can be concisely represented with highly modular, overlapping task-positive/negative pairs of sub-networks.
doi:10.1109/PRNI.2012.25
PMCID: PMC4145006  PMID: 25178438
Resting state fMRI; functional connectivity; sparse modeling; K-SVD
15.  Multi-Kernel Classification for Integration of Clinical and Imaging Data: Application to Prediction of Cognitive Decline in Older Adults 
Diagnosis of neurologic and neuropsychiatric disorders typically involves considerable assessment including clinical observation, neuroimaging, and biological and neuropsychological measurements. While it is reasonable to expect that the integration of neuroimaging data and complementary non-imaging measures is likely to improve early diagnosis on individual basis, due to technical challenges associated with the task of combining different data types, medical image pattern recognition analysis has been largely focusing solely on neuroimaging evaluations. In this paper, we explore the potential of integrating neuroimaging and clinical information within a pattern classification framework, and propose that the multi-kernel learning (MKL) paradigm may be suitable for building a multimodal classifier of a disorder, as well as for automatic identification of the relevance of each information type. We apply our approach to the problem of detecting cognitive decline in healthy older adults from single-visit evaluations, and show that the performance of a classifier can be improved when nouroimaging and clinical evaluations are used simultaneously within a MKL-based classification framework.
doi:10.1007/978-3-642-24319-6_4
PMCID: PMC4137979  PMID: 25147874
Multi-Kernel Learning (MKL); Normal aging; MRI
16.  Use of Neuroanatomical Pattern Classification to Identify Subjects in At-Risk Mental States of Psychosis and Predict Disease Transition 
Archives of general psychiatry  2009;66(7):700-712.
Context
Identification of individuals at high risk of developing psychosis has relied on prodromal symptomatology. Recently, machine learning algorithms have been successfully used for magnetic resonance imaging–based diagnostic classification of neuropsychiatric patient populations.
Objective
To determine whether multivariate neuroanatomical pattern classification facilitates identification of individuals in different at-risk mental states (ARMS) of psychosis and enables the prediction of disease transition at the individual level.
Design
Multivariate neuroanatomical pattern classification was performed on the structural magnetic resonance imaging data of individuals in early or late ARMS vs healthy controls (HCs). The predictive power of the method was then evaluated by categorizing the baseline imaging data of individuals with transition to psychosis vs those without transition vs HCs after 4 years of clinical follow-up. Classification generalizability was estimated by cross-validation and by categorizing an independent cohort of 45 new HCs.
Setting
Departments of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany.
Participants
The first classification analysis included 20 early and 25 late at-risk individuals and 25 matched HCs. The second analysis consisted of 15 individuals with transition, 18 without transition, and 17 matched HCs.
Main Outcome Measures
Specificity, sensitivity, and accuracy of classification.
Results
The 3-group, cross-validated classification accuracies of the first analysis were 86% (HCs vs the rest), 91% (early at-risk individuals vs the rest), and 86% (late at-risk individuals vs the rest). The accuracies in the second analysis were 90% (HCs vs the rest), 88% (individuals with transition vs the rest), and 86% (individuals without transition vs the rest). Independent HCs were correctly classified in 96% (first analysis) and 93% (second analysis) of cases.
Conclusions
Different ARMSs and their clinical outcomes may be reliably identified on an individual basis by assessing patterns of whole-brain neuroanatomical abnormalities. These patterns may serve as valuable biomarkers for the clinician to guide early detection in the prodromal phase of psychosis.
doi:10.1001/archgenpsychiatry.2009.62
PMCID: PMC4135464  PMID: 19581561
17.  PORTR: Pre-Operative and Post-Recurrence Brain Tumor Registration 
We propose a new method for deformable registration of pre-operative and post-recurrence brain MR scans of glioma patients. Performing this type of intra-subject registration is challenging as tumor, resection, recurrence, and edema cause large deformations, missing correspondences, and inconsistent intensity profiles between the scans. To address this challenging task, our method, called PORTR, explicitly accounts for pathological information. It segments tumor, resection cavity, and recurrence based on models specific to each scan. PORTR then uses the resulting maps to exclude pathological regions from the image-based correspondence term while simultaneously measuring the overlap between the aligned tumor and resection cavity. Embedded into a symmetric registration framework, we determine the optimal solution by taking advantage of both discrete and continuous search methods. We apply our method to scans of 24 glioma patients. Both quantitative and qualitative analysis of the results clearly show that our method is superior to other state-of-the-art approaches.
doi:10.1109/TMI.2013.2293478
PMCID: PMC4134002  PMID: 24595340
Brain tumor magnetic resonance imaging (MRI); deformable registration; discrete-continuous optimization; tumor growth model; tumor segmentation
18.  A composite multivariate polygenic and neuroimaging score for prediction of conversion to Alzheimer's disease 
Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) are characterized by widespread pathological changes in the brain. At the same time, Alzheimer's disease is heritable with complex genetic underpinnings that may influence the timing of the related pathological changes in the brain and can affect the progression from MCI to AD. In this paper, we present a multivariate imaging genetics approach for prediction of conversion to Alzheimer's disease in patients with mild cognitive impairment. We employ multivariate pattern recognition approaches to obtain neuroimaging and polygenic discriminators between the healthy individuals and AD patients. We then design, in a linear manner, a composite imaging-genetic score for prediction of conversion to Alzheimer's disease in patients with mild cognitive impairment. We apply our approach within the Alzheimer's Disease Neuroimaging Initiative and show that the integration of polygenic and neuroimaging information improves prediction of conversion to AD.
doi:10.1109/PRNI.2012.9
PMCID: PMC4041795  PMID: 24899230
imaging genetics; multivariate analysis; pattern classification; Alzheimer's disease; mild cognitive impairment
19.  Longitudinal imaging pattern analysis (SPARE-CD index) detects early structural and functional changes before cognitive decline in healthy older adults 
Neurobiology of aging  2012;33(12):2733-2745.
This article investigates longitudinal imaging characteristics of early cognitive decline during normal aging, leveraging on high-dimensional imaging pattern classification methods for the development of early biomarkers of cognitive decline. By combining magnetic resonance imaging (MRI) and resting positron emission tomography (PET) cerebral blood flow (CBF) images, an individualized score is generated using high-dimensional pattern classification, which predicts subsequent cognitive decline in cognitively normal older adults of the Baltimore Longitudinal Study of Aging. The resulting score, termed SPARE-CD (Spatial Pattern of Abnormality for Recognition of Early Cognitive Decline), analyzed longitudinally for 143 cognitively normal subjects over 8 years, shows functional and structural changes well before (2.3–2.9 years) changes in neurocognitive testing (California Verbal Learning Test [CVLT] scores) can be measured. Additionally, this score is found to be correlated to the [11C] Pittsburgh compound B (PiB) PET mean distribution volume ratio at a later time. This work indicates that MRI and PET images, combined with advanced pattern recognition methods, may be useful for very early detection of cognitive decline.
doi:10.1016/j.neurobiolaging.2012.01.010
PMCID: PMC4023476  PMID: 22365049
Cognitive impairment; Magnetic resonance imaging; Positron emission tomography; Support vector machines; Classification
20.  Spatio-temporal Analysis of Brain MRI Images Using Hidden Markov Models 
A rapidly increasing number of medical imaging studies is longitudinal, i.e. involves series of repeated examinations of the same individuals. This paper presents a methodology for analysis of such 4D images, with brain aging as the primary application. An adaptive regional clustering method is first adopted to construct a spatial pattern, in which a measure of correlation between morphological measurements and a continuous patient’s variable (age in our case) is used to group brain voxels into regions; Secondly, a dynamic probabilistic Hidden Markov Model (HMM) is created to statistically analyze the relationship between spatial brain patterns and hidden states; Thirdly, parametric HMM models under a bagging framework are used to capture the changes occurring with time by decoding the hidden states longitudinally. We apply this method to datasets from elderly individuals, and test the effectiveness of this spatio-temporal model in analyzing the temporal dynamics of spatial aging patterns on an individual basis. Experimental results show this method could facilitate the early detection of pathological brain change.
PMCID: PMC3993993  PMID: 20879311
21.  Functional Maturation of the Executive System during Adolescence 
The Journal of Neuroscience  2013;33(41):16249-16261.
Adolescence is characterized by rapid development of executive function. Working memory (WM) is a key element of executive function, but it is not known what brain changes during adolescence allow improved WM performance. Using a fractal n-back fMRI paradigm, we investigated brain responses to WM load in 951 human youths aged 8–22 years. Compared with more limited associations with age, WM performance was robustly associated with both executive network activation and deactivation of the default mode network. Multivariate patterns of brain activation predicted task performance with a high degree of accuracy, and also mediated the observed age-related improvements in WM performance. These results delineate a process of functional maturation of the executive system, and suggest that this process allows for the improvement of cognitive capability seen during adolescence.
doi:10.1523/JNEUROSCI.2345-13.2013
PMCID: PMC3792462  PMID: 24107956
22.  Unsupervised Learning of Functional Network Dynamics in Resting State fMRI 
Research in recent years has provided some evidence of temporal non-stationarity of functional connectivity in resting state fMRI. In this paper, we present a novel methodology that can decode connectivity dynamics into a temporal sequence of hidden network “states” for each subject, using a Hidden Markov Modeling (HMM) framework. Each state is characterized by a unique covariance matrix or whole-brain network. Our model generates these covariance matrices from a common but unknown set of sparse basis networks, which capture the range of functional activity co-variations of regions of interest (ROIs). Distinct hidden states arise due to a variation in the strengths of these basis networks. Thus, our generative model combines a HMM framework with sparse basis learning of positive definite matrices. Results on simulated fMRI data show that our method can effectively recover underlying basis networks as well as hidden states. We apply this method on a normative dataset of resting state fMRI scans. Results indicate that the functional activity of a subject at any point during the scan is composed of combinations of overlapping task-positive/negative pairs of networks as revealed by our basis. Distinct hidden temporal states are produced due to a different set of basis networks dominating the covariance pattern in each state.
PMCID: PMC3974209  PMID: 24683988
resting state fMRI; functional connectivity; temporal network dynamics
23.  Neuronal injury biomarkers and prognosis in ADNI subjects with normal cognition 
Introduction
Based on previous studies, a preclinical classification for Alzheimer’s disease (AD) has been proposed. However, 1) specificity of the different neuronal injury (NI) biomarkers has not been studied, 2) subjects with subtle cognitive impairment but normal NI biomarkers (SCINIB) have not been included in the analyses and 3) progression to mild cognitive impairment (MCI) or dementia of the AD type (DAT), referred to here as MCI/DAT, varies between studies. Therefore, we analyzed data from 486 cognitively normal (CN) and 327 DAT subjects in the AD Neuroimaging Initiative (ADNI)-1/GO/2 cohorts.
Results
In the ADNI-1 cohort (median follow-up of 6 years), 6.3% and 17.0% of the CN subjects developed MCI/DAT after 3 and 5 years follow-up, respectively. NI biomarker cutoffs [structural magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET) and cerebrospinal fluid (CSF) tau] were established in DAT patients and memory composite scores were calculated in CN subjects in a cross-sectional sample (n = 160). In the complete longitudinally followed CN ADNI cohort (n = 326, median follow-up of 2 years), CSF and MRI values predicted an increased conversion to MCI/DAT. Different NI biomarkers showed important disagreements for classifying subjects as abnormal NI [kappa = (−0.05)-(0.33)] and into AD preclinical groups. SCINIB subjects (5.0%) were more prevalent than AD preclinical stage 3 subjects (3.4%) and showed a trend for increased progression to MCI/DAT.
Conclusions
Different NI biomarkers lead to different classifications of ADNI subjects, while structural MRI and CSF tau measures showed the strongest predictive value for progression to MCI/DAT. The newly defined SCINIB category of ADNI subjects is more prevalent than AD preclinical stage individuals.
doi:10.1186/2051-5960-2-26
PMCID: PMC4008258  PMID: 24602322
Dementia; Alzheimer’s disease; Magnetic resonance imaging; Cerebrospinal fluid; Amyloid beta; Tau
24.  Neuroanatomical Classification in a Population-Based Sample of Psychotic Major Depression and Bipolar I Disorder with 1 Year of Diagnostic Stability 
BioMed Research International  2014;2014:706157.
The presence of psychotic features in the course of a depressive disorder is known to increase the risk for bipolarity, but the early identification of such cases remains challenging in clinical practice. In the present study, we evaluated the diagnostic performance of a neuroanatomical pattern classification method in the discrimination between psychotic major depressive disorder (MDD), bipolar I disorder (BD-I), and healthy controls (HC) using a homogenous sample of patients at an early course of their illness. Twenty-three cases of first-episode psychotic mania (BD-I) and 19 individuals with a first episode of psychotic MDD whose diagnosis remained stable during 1 year of followup underwent 1.5 T MRI at baseline. A previously validated multivariate classifier based on support vector machine (SVM) was employed and measures of diagnostic performance were obtained for the discrimination between each diagnostic group and subsamples of age- and gender-matched controls recruited in the same neighborhood of the patients. Based on T1-weighted images only, the SVM-classifier afforded poor discrimination in all 3 pairwise comparisons: BD-I versus HC; MDD versus HC; and BD-I versus MDD. Thus, at the population level and using structural MRI only, we failed to achieve good discrimination between BD-I, psychotic MDD, and HC in this proof of concept study.
doi:10.1155/2014/706157
PMCID: PMC3915628  PMID: 24575411
25.  IDENTIFYING PATTERNS IN TEMPORAL VARIATION OF FUNCTIONAL CONNECTIVITY USING RESTING STATE FMRI 
Estimating functional brain networks from fMRI data has been the focus of much research in recent years. Low sample sizes (time-points) and high dimensionality of fMRI has restricted estimation to a temporally averaged connectivity matrix per subject, due to which the dynamics of functional connectivity is largely unknown. In this paper, we propose a novel method based on constrained matrix factorization that addresses two major issues. Firstly, it finds a set of basis networks that are the semantic parts of the time-varying whole-brain functional networks. The whole-brain network at any point in time, for any subject, is a non-negative combination of these basis networks. Secondly, significant dimensionality reduction is achieved by projecting the data onto this basis, facilitating subsequent analysis of temporal dynamics. Results on simulated fMRI data show that our method can effectively recover underlying basis networks. We apply this method on a normative dataset of resting state fMRI scans. Results indicate that the functional connectivity of a subject at any point during the scan is composed of combinations of overlapping task-positive/negative pairs of sub-networks.
doi:10.1109/ISBI.2013.6556667
PMCID: PMC3892432  PMID: 24443693
resting state fMRI; functional connectivity; temporal network dynamics

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