Brain functional connectivity network (BFCN) has been widely applied to identify biomarkers for the brain function understanding and brain diseases analysis.
Building a biologically meaningful brain network is a crucial work in these applications. For this task, sparse learning has been widely applied for the network construction. If multiple time-point data is added to the brain imaging application, the disease progression pattern in the longitudinal analysis can be better revealed.
A novel longitudinal analysis for MCI classification is devised based on resting-state functional magnetic resonating imaging (rs-fMRI). Specifically, this paper proposes a novel multi-task learning method to integrate fused penalty by regularization. In addition, a novel objective function is developed for fused sparse learning via smoothness constraint.
The proposed method achieves the best classification performance with an accuracy of 95.74% for baseline and 93.64% for year 1 data.
The experimental results show that our proposed method achieves quite promising classification performance.
With a progressive decline of memory and cognitive function, Alzheimer’s disease (AD) and its prodromal stage, mild cognitive impairment (MCI), are incurable neurodegenerative disease [1, 2]. Both AD and MCI are the main dementia leading to about 60–80% of dementia cases in the worldwide . MCI is convertible to AD with an average rate of 10–15% . Since MCI is misdiagnosed most of time due to explicit symptoms, the prompt treatment and monitor of AD progression before its onset is highly desirable . Currently, various imaging modalities have been widely applied for AD studies (e.g., structural magnetic resonating imaging (MRI) [6, 7, 8, 9, 10], positron emission tomography (PET) [11, 12, 13], pathological amyloid depositions measured through cerebrospinal fluid (CSF) [14, 15, 16, 17], and resting-state functional MRI (rs-fMRI)). Rs-fMRI is able to check functional integration and separation of brain networks disrupted by MCI and establish functional connectivity (FC) among brain regions to characterize MCI [18, 19]. Actually, FC is denoted as the temporal correlation of blood-oxygenation-level-dependent (BOLD) time series between two brain regions . The rs-fMRI is promising for brain disease identification by providing unique information via FC network. The brain FC network (BFCN) study based on rs-fMRI has played an increasing important role in identifying biomarkers for neurological disorders . Hence, it is of great interest to develop early MCI diagnosis method to delay AD progression and treat this dementia.
Up to now, a myriad of FC modelling methods have been developed [22, 23, 24]. Namely, different regions-of-interest (ROIs) are parcellated from brain regions to estimate the BOLD time series of ROI. For example, the pairwise Pearson’s correlation (PC) among different brain regions is one of the widely applied FC modelling algorithms to construct brain regions for MCI topological properties revelation . However, PC focuses on pairwise relationship only, which fails to consider the interaction among multiple brain regions . By contrast, another widely applied method is to establish FC network via sparse representation (SR) . This sparse estimation is based on partial correlation via regularization to construct the relationship among certain ROIs while removing other ROIs’ effects. SR network has been applied in AD and MCI by constructing brain networks [27, 28, 29]. However, the existing research not only uses inherently sparse method, but also incorporates group structure. Therefore, it is interesting to integrate both information.
It is known that machine learning techniques can make use of feature extracted from BFCN for MCI patient identification with a relatively high accuracy [18, 28, 30, 31, 32, 33]. Although the conventional studies mostly focused on single time point information from brain regions, it is limited due to lack of longitudinal analysis. To enhance the diagnostic performance, multiple time point networks can model disease progression comprehensively and effectively [34, 35]. In the literature, longitudinal study for disease progression modelling has become a hot topic due to its effectiveness [4, 34, 36, 37]. For example, Zhou et al.  proposed to model AD progression based on a novel designed convex fused learning for score prediction and achieved remarkable results. Huang et al.  predicted the longitudinal score using weighted random forest and obtained superior results than the traditional study. Jie et al.  proposed a temporal smooth framework for longitudinal score prediction. In spite of these efforts, the previous studies mainly focused on the score prediction based on MRI or PET data only . It is argued that the FC network from rs-fMRI data can be more effective for disease progression study . In view of this, our study concentrates on the longitudinal analysis for MCI identification via rs-fMRI data. To our best knowledge, this is the first longitudinal analysis of MCI disease modelling based on FC network of rs-fMRI data.
To characterize the complex MCI disease, we propose to develop a novel brain network model based on multi-task fused learning with smoothness constraint. Specifically, we devise a network to take advantage of relationship of successive time points. A novel framework for longitudinal functional analysis of MCI disease is developed. Moreover, we perform feature selection via the least absolute shrinkage and selection operator (LASSO)  to identify the most informative features, and the final selected features are fed into support vector machine (SVM) for MCI identification . We evaluate our proposed method based on the Alzheimer’s Disease Neuroimaging Initiative Phase-2 (ADNI-2) database. Our experiments confirm that our method outperforms the traditional methods for MCI diagnosis.
Figure 1 shows the flowchart of the proposed method. We preprocess multiple time points rs-fMRI data to build the FC network.
2.2Subjects and data acquisition
Our study is based on the data obtained from the ADNI database created and updated since 2004. The six-year study received $60 million from the public and private sectors, including the National Institute of Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and the Food and Drug Administration. The main goal of the ADNI database is to use the continuous MRI and PET images as well as other biomarkers for the clinical and neuropsychological assessment of early AD and MCI progression. Specific and sensitive markers for the detection of early AD progression are designed to help scholars and clinical experts develop new therapies and monitor their effectiveness, which can effectively reduce the cost and time of clinical diagnosis. A large number of academic institutions and private companies have worked together to build the ADNI database and recruited subjects from over 50 sites in the USA and Canada . For up-to-date information, please refer to www.adni-info.org.
The data exploited in the preparation of this paper is acquired from the ADNI Phase-2 (ADNI-2) database. There are 24 MCI patients and 23 normal controls (NCs) in our study, which contains two time points (baseline and year1) rs-fMRI data. Every subject is scanned using 3.0T Philips Achieva scanners with matched age and gender and the slice thickness is 3.3 mm. The Raw Digital Imaging and Communications in Medicine (DICOM) MRI scans are obtained from the public ADNI site (adni.loni.usc.edu). The quality of these scans is checked, the spatial distortion caused by B1 field inhomogeneity and gradient nonlinearity are automatically corrected.
2.3Image preprocessing and feature extraction
All subjects used the 3.0T Philips Achieva to scan at different centres with the following parameters: TR/TE 3000/30 mm, rollover angle 80, imaging matrix 64 64, 48 slices,140 volumes, body thickness 3.3 mm. The SPM8 software package is used for preprocessing the rs-fMRI data. Prior to any further processing, the first 4 rs-fMRI volumes of every subject are discarded to keep the magnetization equilibrium. The remaining volumes are then fixed for the interleaved order of the slices during the echo plane scan. This correction guarantees that the data on every slice corresponds to the same point. The interpolation time point is selected as the TR/2 time so that the relative error of every TR is minimized. After obtaining time delay correction, the slice timing to correct rs-fMRI time-series of every subject are realigned. The realignment utilizes a rigid body spatial transformation and a least squares approach. The first volume is used as a reference for entire subsequent volumes to be readjusted. This step discards the head movement illusion in the rs-fMRI time series. There is no significant group difference in the head movement of whole participants utilized in the study. After readjustment, the volumes are resliced so that they can match the first volume voxel-by-voxel. Rs-fMRI images are then normalized to the Montreal Neurological Institute (MNI) space with resolution of 3 3 3 mm .
The rs-fMRI is divided into 116 brain regions using the automatic anatomical labelling (AAL) template. FSL software is used for pre-processing in our experiment . The average rs-fMRI time series of each brain region is also filtered by high pass filtering. In addition, we regressed out head movement parameters, mean BOLD time series of the white matter and the cerebrospinal fluid. The mean of BOLD signal in every region of interest (ROI) is used as features. Accordingly, the original rs-fMRI signal is denoted by 116 ROIs (i.e.,116 nodes) and connections between each pair of 116 ROIs (i.e., the edges connecting them). PC of two mean time series between a pair of ROIs is computed to measure the connection strength.
2.4Multitask fused sparse regression model
The dimension curse is always an issue in modelling rs-fMRI dataset. To address it, it is argued that group lasso is an effective way. A small number of features of specific groups can be identified by the group lasso to construct connectivity map using non-zero weights of all predictors. There are differences in the connection between MCI and NC as indicated in .
Assuming there are subjects and each brain is divided into ROIs using AAL template, a response vector with length regional mean time series of the -th ROI is represented as: , and the represents a predictor data matrix of a subject. is data matrix of -th ROI (the whole BOLD time series except for -th ROI), is weighting regression coefficient vector, . Then the key step of constructing the BFCN for this subject is to estimate the FC matrix , nodes (i.e., , ) denote all ROIs. There are many researches to construct a sparse network to model the brain region connectivity, and the typical group lasso sparse learning network is formulated as below
where is the group regularization. Specifically, the group regularization is defined as below
where is the group regularization parameter, represents the connectivity coefficients of -th predictor. The utilization of -norm on row vectors groups -th feature in the whole time points by imposing the weights, and the further adoption of -norm jointly selects features via the weights of time points. The group lasso regularization is the traditional sparse regression network, which makes sure that all the regression models in different groups have the shared set of connections. The -norm group penalty imposes every representation coefficient using the same weight. Namely, this -norm treats each ROI in the same way to reconstruct a target ROI. Accordingly, SR model with this objective function is able to reconstruct the target ROI by the ROIs different from the target ROI. In addition, each ROI reconstruction is independent from others.
The main goal in brain disease diagnosis is to enhance the diagnostic performance between NC and MCI, but the group lasso regression model with penalty fails to consider the smooth properties of different time points in the framework. For this reason, we devise a novel framework to jointly learn shared functional brain networks of each subject by the group sparse regularization and fused smoothness information with the devised regularization terms as below:
where is group regularization, and denotes the smoothness regularization. Specifically, the smoothness regularization is defined as below
where and are the parameters of smoothness regularization. The first term, , is the regularization penalty derived from fused LASSO [45, 46], which constrains the diversity between two consecutive weighting vectors from successive time points to be as small as possible. Because of -norm used in this fused smoothness term, the sparsity of weighting vectors difference is encouraged since lots of zero components will occur in the imparity vectors of weighting. Namely, due to the regularization of the smoothness fusion, a large number of components from the adjacent weight vectors will be the same. The informative features will be selected due to non-zero weights in our classification task. In addition, the last term, , is the target smoothness, which encourages the difference of two consecutive models of continuous time points as small as possible. When the smoothness regularization parameters and are zero, the proposed method is the conventional group lasso method . We smooth the connectivity coefficients of the subjects at different time points by introducing the fused smoothness terms. In addition, this learning framework imposes a high degree of constraints through regularization terms. We call this sparse learning model as multi-task fused sparse regression model (MFSR).
Our objective function simultaneously includes both group and smoothness regularizations, and the iterative projected gradient descent algorithm is used to minimize the objective function. Specifically, the objective function in Eq. (3) is divided into the smoothing term
and the non-smoothing term
In each iteration , two steps are contained in the projected gradient descent. Let the gradient of at denote as (), and the step size denote as and be determined via line search. The first step is denoted as
The second step is as follow
For the non-smooth term in Eq. (8), we can calculate sequentially the proximal operator that related with the group Lasso constraints  and the fused Lasso constraints . We use the techniques discussed in  to further accelerate the above gradient. We compute the search point to perform gradient descent via
where is a pre-defined variable and is defined as
Finally, the new approximate solution is obtained.
3.Experiments and results
In our experiment, our proposed method is implemented using Matlab 2015a software. The sparse regression and classification are implemented by SLEP and LibSVM toolboxes , respectively. As our data size is small, we adopt the leave-one-out cross validation (LOOCV) scheme to evaluate the proposed method. The hyper parameters in each method are empirically set by the greedy search strategy to select the optimal parameters. For example, we obtain the optimal values of , and through the exhaustive search strategy from to . In order to evaluate the performance of various methods, we use the following evaluation metrics: accuracy (ACC), area under receiver operating characteristic (ROC) curve (AUC), sensitivity (SEN), specificity (SPEC), Youden’s Index (Youden), F1-score (F1), and balanced accuracy (BAC). We compare the proposed MFSR network with the related networks such as Baseline PC network, Baseline SR network, Baseline MFSR network, Year 1 PC network, Year 1 SR network and Year 1 MFSR network.
In order to assess the efficacy of our proposed MFSR method, we compare our method with the typical methods including PC and SR. Moreover, we conduct two groups of experiments on the multiple time points data of the ADNI-2 database, i.e., baseline and year 1 classification. The experimental results are displayed in Figs 2, 3 and Table 1, respectively. The proposed network achieves the best classification performance with an accuracy of 95.74% for baseline and 93.64% for year 1 data. We can see that our proposed network outperforms other competing networks in terms of classification results. The reason of our proposed brain network achieves better classification results is that it can overcome the previous network’s drawbacks. It is clear that multi-task learning is better than each individual task because it can uncover the potential relationships among multiple time points rather than the simple averaging. By observing the relationship of successive ROIs, we can see that the MFSR model outperforms the traditional SR and PC models in both baseline and year 1 data, which confirms that multiple time-point constrained network is beneficial for MCI classification. Another encouraging phenomenon is that the impact of time changes on the classification performance is less sensitive. It can be seen that the results of year 1 are slightly worse than that of baseline. We can see that our proposed group sparse learning with smoothing constraints is quite effective.
We randomly select MCI and NC patients from the database to compare the performance of different methods in terms of network. From Fig. 4, we can see that the conventional networks achieve similar results between MCI and NC. Our proposed MFSR network shows more block structures and clear layouts, which can reveal the differences between MCI and NC.
Figure 5a and b show the top 10 selected brain regions in the baseline and year 1 data, respectively. Different colors represent 10 different selected brain regions of the highest frequency for clear discrimination. The experimental results show that baseline and year 1 data select several common regions as important features for MCI classification. In addition, it is obvious that the frontal and temporal features are frequently identified. The selected brain regions including the temporal inferior frontal gyrus, supplementary motor area, insula, frontal middle gyrus, middle temporal gyrus, superior gyrus, can be used for potential clinical diagnosis. A group of brain regions in the temporal pole, medial orbitofrontal cortex, and bilateral fusiform play an important role in the MCI identification. The connection relationship of the 5 regions with the highest probability is clearly shown in Fig. 6, where different nodes denote ROIs, and edges represent the degree of association of different ROIs. The thicker the connection, the greater the association weight between the ROIs. The blue and yellow lines represent the connection of the 5 selected brain regions in the year 1 and baseline data, respectively. ROIs connection relationships are displayed in Fig. 7. We find that gyrus, and temporal gyrus regions are identified for MCI diagnosis, which are in line with the findings of the most selected regions in MCI in previous studies. Overall, the top selected most discriminative brain regions are closely related with MCI pathology and consistent with previous clinical findings as well [28, 29].
In this paper, the longitudinal analysis and network modeling are combined to develop a new multi-task sparse learning framework for MCI disease identification. Compared with other widely used methods, our proposed method can model the complex brain network more accurately. The longitudinal analysis via complex brain network is quite effective for the MCI prediction. The experimental results show that the recognition of MCI at multiple time points is quite effective. In our future work, we will strive to add more modalities and smoothing constraints to further enhance the accuracy of MCI diagnosis. Also, the graph theory and high-order statistics (mean clustering coefficients, covariance of the clustering) can be incorporated into our framework to improve the performance of the entire framework as well.
This study was funded partly by National Natural Science Foundation of China (Nos. 61501305 and 81771922), National Natural Science Foundation of Guangdong Province (Nos. 2017A030313377 and 2016A030313047), Shenzhen Key Basic Research Project (Nos. JCYJ20140415092628046, JCYJ20170302153337765, JCYJ20150525092940982 and 201502007), Shenzhen Peacock Plan (No. KQTD2016053112051497), and the National Natural Science Foundation of Shenzhen University (Nos. 2016077 and 201565 and 2016089).
Conflict of interest
None to report.
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