A PROBABILISTIC MODEL OF FUNCTIONAL BRAIN CONNECTIVITY NETWORK FOR DISCOVERING NOVEL BIOMARKERS

Jiang Bian1, Mengjun Xie2, Umit Topaloglu1 and Josh Cisler3

1Division of Biomedical Informatics 3Brain Image Research Center

University of Arkansas for Medical Sciences University of Arkansas at Little Rock

2Computer Science

Outline
Brain connectivity networks and real-world complex networks A probabilistic model of the human brain connectom from zero and one to a probabilistic model using network characteristics as potential biomarkers Evaluation and results Discussion and future work

brain connectivity networks

Brain can be modeled as a massive parallel computing network. Three types of brain connectivity networks: structure network, constrained by physical structure of the brain (MRI, DTI) functional network, coherence or correlation between brain regions (resting-state fMRI/MEG) effective network, covariance modeling, Granger causality (tasked-based EEG/fMRI)
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complex networks
Many real-world complex networks including the brain networks have similar topological features: small-world: high clustering coefficient, but relatively low characteristic path length
(Watts and Strogatz, 1998)

scale-free: highly connected hubs (Barabsi and Albert, 1999)

an image of the Internet from the Internet...
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functional brain connectivity

images from the internet...

functional brain networks

fMRI data gives a set of timecourses of the BOLD signals of each voxel (e.g., 3mm3) within the gray matter Through computing the covariance of two voxels timecourses, we can infer whether the two are functionally connected Typically, neuroscientists work with ROIs (a collection of voxels)
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a probabilistic model
Existing connectivity studies assume temporal stability of two ROIs, as they compute the correlation coefficient using the entire timecourses We need to consider the temporal fluctuations of the connectivities between ROIs, as hinted by recent neuroscience studies (Stamoulis et. al., 2010 and Whitlow et. al., 2011) Therefore, we propose to consider the frequency of functional connections between brain regions over time and regard the frequent connections as strong and important to the operation of the overall brain network
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a probabilistic model
s1-2 = 4/8 = 0.5 se(i,j) = |e(i,j)|/|TW| 0 1 0

{
1 0 1 1 0

conventional vs. probabilistic

frequency graph

b) strong-edge graph

a) conventional graph
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network characteristics as biomarkers

A number of studies (e.g., Calhoun et. al., 2008, Craddock et. al., 2009) have shown that neural network organization patterns can be used to differentiate disease states.

+ Network characteristics and the topology of a network can be

quantitatively measured as clustering coefficient, node betweenness centrality, characteristic path length, etc. to tell whether I have xyz? Bonus: the probabilistic model vs. the conventional method

= Why not build a prediction model using these network features

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evaluation methods
We study the subjects of Major Depression Disorder (MDD) 19 health women with no MDD history in the control group; 19 women with MDD (6 with current MDD, 13 with MDD history) as the diseased group; MDD was characterized with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). Both groups underwent 7.2 mins resting-state fMRI scan. We selected 11 ROIs of the default mode network (DMN) based on previous neuroscience studies. PCC, rPG, lPG, SCC, rPC, lPC, rITG, lITG, rSFG, lSFG, MPC

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network measures
For each subject's brain connectivity network, we compute the following network indices: degree (or strength in a weighted graph), betweenness centrality, closeness centrality, local and global clustering coefficient, and global characteristic path length.
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SVM classifiers
We use the network features to build Support Vector Machines (SVMs) for both the conventional and our probabilistic model. Standard SVM techniques have been considered: scaling, grid-based kernel parameter search and feature selection using F-test. Evaluation methods: Bootstrap the sample 1000 times and during each iteration: 2/3 is used for training, and the rest1/3 is kept for testing. We measure the prediction accuracy and the ROC area under the curve (AUC) at each iteration and take the average as the final result.
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results
vs.
b) the strong-edge model a) the conventional model
(Accuracy: 76%, AUC: 0.87)
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(Accuracy: 89%, AUC: 0.96)

discussion
A number of free variables can influence the accuracy of brain network models and consequently affect the classifiers' performance. In the conventional method: the choice of the correlation coefficient threshold T that determines whether we shall draw an edge between two voxels (ROIs); determined by the targeted density, and we choose (0.37 ~ 0.5) followed existing studies. In the strong-edge (probabilistic) model: the choice of the density value is relaxed and we can choose a high density value (0.76); however, we introduce the Sminsup that determines the cut-off frequency for defining an edge to be strong (less important for the classifier)

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discussion and future work

A number of biomarkers are identified, e.g., the betweenness centrality of rPG; and the clustering coefficient of lSFG. These biomarkers have plausible explanations within the context of neuroscience. e.g., Additionally, the link between the left superior frontal gyrus and the right insula is also reduced... (Tao et al. 2011, Nature) Future work: Test the theory on other brain diseases (preliminary results on a drug-addict dataset are promising). Can we work on the voxel-level data? Pros: No expert needed to pick a ROI-based neural network Cons: Computationally expensive.

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Q & A?
jbian@uams.edu

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