Energy landscape analysis of brain network dynamics in Alzheimer's disease.

Background: Alzheimer's disease (AD) is a common neurodegenerative dementia, characterized by abnormal dynamic functional connectivity (DFC). Traditional DFC analysis, assuming linear brain dynamics, may neglect the complexity of the brain's nonlinear interactions. Energy landscape analysis offers a holistic, nonlinear perspective to investigate brain network attractor dynamics, which was applied to resting-state fMRI data for AD in this study. Methods: This study utilized resting-state fMRI data from 60 individuals, comparing 30 Alzheimer's patients with 30 controls, from the Alzheimer's Disease Neuroimaging Initiative. Energy landscape analysis was applied to the data to characterize the aberrant brain network dynamics of AD patients. Results: The AD group stayed in the co-activation state for less time than the healthy control (HC) group, and a positive correlation was identified between the transition frequency of the co-activation state and behavior performance. Furthermore, the AD group showed a higher occurrence frequency and transition frequency of the cognitive control state and sensory integration state than the HC group. The transition between the two states was positively correlated with behavior performance. Conclusion: The results suggest that the co-activation state could be important to cognitive processing and that the AD group possibly raised cognitive ability by increasing the occurrence and transition between the impaired cognitive control and sensory integration states.

Improved brain community structure detection by two-step weighted modularity maximization.

The human brain can be regarded as a complex network with interacting connections between brain regions. Complex brain network analyses have been widely applied to functional magnetic resonance imaging (fMRI) data and have revealed the existence of community structures in brain networks. The identification of communities may provide insight into understanding the topological functions of brain networks. Among various community detection methods, the modularity maximization (MM) method has the advantages of model conciseness, fast convergence and strong adaptability to large-scale networks and has been extended from single-layer networks to multilayer networks to investigate the community structure changes of brain networks. However, the problems of MM, suffering from instability and failing to detect hierarchical community structure in networks, largely limit the application of MM in the community detection of brain networks. In this study, we proposed the weighted modularity maximization (WMM) method by using the weight matrix to weight the adjacency matrix and improve the performance of MM. Moreover, we further proposed the two-step WMM method to detect the hierarchical community structures of networks by utilizing node attributes. The results of the synthetic networks without node attributes demonstrated that WMM showed better partition accuracy than both MM and robust MM and better stability than MM. The two-step WMM method showed better accuracy of community partitioning than WMM for synthetic networks with node attributes. Moreover, the results of resting state fMRI (rs-fMRI) data showed that two-step WMM had the advantage of detecting the hierarchical communities over WMM and was more insensitive to the density of the rs-fMRI networks than WMM.

Correction to: Improved dynamic functional connectivity estimation with an alternating hidden Markov model.

[This corrects the article DOI: 10.1007/s11571-022-09874-3.].

Improved dynamic functional connectivity estimation with an alternating hidden Markov model.

Dynamic functional connectivity (DFC) analysis has been widely applied to functional magnetic resonance imaging (fMRI) data to reveal the time-varying functional interactions between brain regions. Although the sliding window (SW) method is popular for DFC analysis, the selection of window length is hard, and the temporal resolution is limited by the window length. The hidden Markov model (HMM) without the limitation of window length has been proven to be able to estimate time-varying brain states from fMRI data. However, HMM tends to be overfitted in DFC analysis of fMRI data because of the high spatial dimension and the limited sample size of fMRI data. In this study, we proposed an alternating HMM (aHMM) method that used the functional connectivity estimation of SW to initialize the covariance matrix of HMM and adopted an alternating HMM procedure to reduce the number of parameters during each optimization. The simulated and real fMRI resting data from the Human Connectome Projects showed that aHMM produced better robustness to noise, parameter number and sample size in DFC estimation than SW and HMM. For the real fMRI resting data of cerebral small vessel disease (CSVD), results of aHMM revealed that amnesia and mild cognitive impairment (aMCI) caused the CSVD with aMCI (CSVD-aMCI) group tended to spend more time on the brain state with overall weak connections and less time on the state with overall strong connections than the CSVD-controls. Moreover, CSVD-aMCI showed significantly lower connectivity amplitude and higher connectivity fluctuation than CSVD-control. In contrast, HMM did not detect intergroup differences of the connectivity amplitude and fluctuations and SW did not detect intergroup differences of connectivity fluctuations and fraction of time. The results further indicated that aHMM outperformed HMM and SW in detecting inter-group differences of temporal properties of DFC and connectivity fluctuations. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-022-09874-3.

Assessment of 3D Visual Discomfort Based on Dynamic Functional Connectivity Analysis with HMM in EEG.

Stereoscopic displays can induce visual discomfort despite their wide application. Electroencephalography (EEG) technology has been applied to assess 3D visual discomfort, because it can capture brain activities with high temporal resolution. Previous studies explored the frequency and temporal features relevant to visual discomfort in EEG data. Recently, it was demonstrated that functional connectivity between brain regions fluctuates with time. However, the relationship between 3D visual discomfort and dynamic functional connectivity (DFC) remains unknown. Although HMM showed advantages over the sliding window method in capturing the temporal fluctuations of DFC at a single time point in functional magnetic resonance imaging (fMRI) data, it is unclear whether HMM works well in revealing the time-varying functional connectivity of EEG data. In this study, the hidden Markov model (HMM) was introduced to DFC analysis of EEG data for the first time and was used to investigate the DFC features that can be used to assess 3D visual discomfort. The results indicated that state 2, with strong connections between electrodes, occurred more frequently in the early period, whereas state 4, with overall weak connections between electrodes, occurred more frequently in the late period for both visual comfort and discomfort stimuli. Moreover, the 3D visual discomfort stimuli caused subjects to stay in state 4 more frequently, especially in the later period, in contrast to the 3D visual comfort stimuli. The results suggest that the increasing occurrence of state 4 was possibly related to visual discomfort and that the occurrence frequency of state 4 may be used to assess visual discomfort.

Altered Dynamic Functional Connectivity in Subcortical Ischemic Vascular Disease With Cognitive Impairment.

Subcortical ischemic vascular disease (SIVD) can cause cognitive impairment and affect the static functional connectivity of resting functional magnetic resonance imaging (fMRI). Numerous previous studies have demonstrated that functional connectivities (FCs) fluctuate dynamically over time. However, little is known about the impact of cognitive impairment on brain dynamic functional connectivity (DFC) in SIVD patients with MCI. In the present study, the DFC analysis method was applied to the resting functional magnetic resonance imaging (fMRI) data of 37 SIVD controls (SIVD-Control) without cognitive impairment, 34 SIVD patients with amnestic MCI (SIVD-aMCI) and 30 SIVD patients with nonamnestic MCI (SIVD-naMCI). The results indicated that the cognitive impairment of SIVD mainly reduced the mean dwell time of State 3 with overall strong positive connections. The reduction degree of SIVD-aMCI was larger than that of SIVD-naMCI. The memory/execution function impairment of SIVD also changed the relationship between the mean dwell time of State 3 and the behavioral performance of the memory/execution task from significant to non-significant correlation. Moreover, SIVD-aMCI showed significantly lower system segregation of FC states than SIVD-Control and SIVD-naMCI. The system segregation of State 5 with overall weak connections was significantly positive correlated with the memory performance. The results may suggest that the mean dwell time of State 3 and the system segregation of State 5 may be used as important neural measures of cognitive impairments of SIVD.

Dynamic Functional Network Connectivity Changes Associated with fMRI Neurofeedback of Right Premotor Cortex.

Neurofeedback of real-time functional magnetic resonance imaging (rtfMRI) can enable people to self-regulate motor-related brain regions and lead to alteration of motor performance and functional connectivity (FC) underlying motor execution tasks. Numerous studies suggest that FCs dynamically fluctuate over time. However, little is known about the impact of neurofeedback training of the motor-related region on the dynamic characteristics of FC underlying motor execution tasks. This study aims to investigate the mechanism of self-regulation of the right premotor area (PMA) on the underlying dynamic functional network connectivity (DFNC) of motor execution (ME) tasks and reveal the relationship between DFNC, training effect, and motor performance. The results indicate that the experimental group spent less time on state 2, with overall weak connections, and more time on state 6, having strong positive connections between motor-related networks than the control group after the training. For the experimental group's state 2, the mean dwell time after the training showed negative correlation with the tapping frequency and the amount of upregulation of PMA. The findings show that rtfMRI neurofeedback can change the temporal properties of DFNC, and the DFNC changes in state with overall weak connections were associated with the training effect and the improvement in motor performance.

3D Contrast Image Reconstruction From Human Brain Activity.

Several studies demonstrated that functional magnetic resonance imaging (fMRI) signals in early visual cortex can be used to reconstruct 2-dimensional (2D) visual contents. However, it remains unknown how to reconstruct 3-dimensional (3D) visual stimuli from fMRI signals in visual cortex. 3D visual stimuli contain 2D visual features and depth information. Moreover, binocular disparity is an important cue for depth perception. Thus, it is more challenging to reconstruct 3D visual stimuli than 2D visual stimuli from the fMRI signals of visual cortex. This study aimed to reconstruct 3D visual images by constructing three decoding models: contrast-decoding, disparity-decoding and contrast-disparity-decoding models, and testing these models with fMRI data from humans viewing 3D contrast images. The results revealed that the 3D contrast stimuli can be reconstructed from the visual cortex. And the early visual regions (V1, V2) showed predominant advantages in reconstructing the contrast in 3D images for the contrast-decoding model. The dorsal visual regions (V3A, V7 and MT) showed predominant advantages in decoding the disparity in 3D images for the disparity-decoding model. The combination of the early and dorsal visual regions showed predominant advantages in decoding both the contrast and disparity for the contrast-disparity-decoding model. The results suggested that the contrast and disparity in 3D images were mainly represented in the early and dorsal visual regions separately. The two visual systems may interact with each other to decode 3D-contrast images.

A semi-blind online dictionary learning approach for fMRI data.

BACKGROUND: Online dictionary learning (ODL) has been applied to extract brain networks from functional magnetic resonance imaging (fMRI) data in recent year. Moreover, the supervised dictionary learning (SDL) that fixed the task stimulus curves as predefined atoms was proposed to improve ODL for functional networks separation. However, SDL cannot estimate the real time courses underlying the brain networks and cannot be applied to the inter-network connectivity analysis. This study aimed at investigating how to add the temporal prior information to ODL to extract the accurate task-related brain networks and the corresponding time courses. NEW METHOD: To improve the performance of ODL, we propose a semi-blind ODL (semi-ODL) method that incorporates temporal prior information of the task paradigm into the dictionary updating process and optimizes the direction of one or more specific atoms "close" to the task time courses. RESULTS: Results of the simulated and real fMRI experiment revealed that semi-ODL extracted more accurate task-related component and time courses than ODL and SDL. For one-task fMRI data, semi-ODL and Infomax-ICA showed similar detection power in most cases. COMPARISON WITH EXISTING METHODS: The semi-ODL outperformed ODL, SDL in robustness to noise, spatial detection power and time course estimation. Moreover, semi-ODL showed comparable performance to Infomax-ICA for one-task fMRI data and outperformed Infomax-ICA in extracting the components related to each task from multi-task fMRI data. CONCLUSIONS: The semi-ODL method is potentially useful to reveal brain networks underlying various cognitive tasks and the interactions between task-related brain networks.

Two-step paretial least square regression classifiers in brain-state decoding using functional magnetic resonance imaging.

Multivariate analysis methods have been widely applied to decode brain states from functional magnetic resonance imaging (fMRI) data. Among various multivariate analysis methods, partial least squares regression (PLSR) is often used to select relevant features for decoding brain states. However, PLSR is seldom directly used as a classifier to decode brain states from fMRI data. It is unclear how PLSR classifiers perform in brain-state decoding using fMRI. In this study, we propose two types of two-step PLSR classifiers that use PLSR/sparse PLSR (SPLSR) to select features and PLSR for classification to improve the performance of the PLSR classifier. The results of simulated and real fMRI data demonstrated that the PLSR classifier using PLSR/SPLSR to select features outperformed both the PLSR classifier using a general linear model (GLM) and the support vector machine (SVM) using PLSR/SPLSR/GLM in most cases. Moreover, PLSR using SPLSR to select features showed the best performance among all of the methods. Compared to GLM, PLSR is more sensitive in selecting the voxels that are specific to each task. The results suggest that the performance of the PLSR classifier can be largely improved when the PLSR classifier is combined with the feature selection methods of SPLSR and PLSR.

Disparity level identification using the voxel-wise Gabor model of fMRI data.

Perceiving disparities is the intuitive basis for our understanding of the physical world. Although many electrophysiology studies have revealed the disparity-tuning characteristics of the neurons in the visual areas of the macaque brain, neuron population responses to disparity processing have seldom been investigated. Many disparity studies using functional magnetic resonance imaging (fMRI) have revealed the disparity-selective visual areas in the human brain. However, it is unclear how to characterize neuron population disparity-tuning responses using fMRI technique. In the present study, we constructed three voxel-wise encoding Gabor models to predict the voxel responses to novel disparity levels and used a decoding method to identify the new disparity levels from population responses in the cortex. Among the three encoding models, the fine-coarse model (FCM) that used fine/coarse disparities to fit the voxel responses to disparities outperformed the single model and uncrossed-crossed model. Moreover, the FCM demonstrated high accuracy in predicting voxel responses in V3A complex and high accuracy in identifying novel disparities from responses in V3A complex. Our results suggest that the FCM can better characterize the voxel responses to disparities than the other two models and V3A complex is a critical visual area for representing disparity information.

Temporally constrained ICA with threshold and its application to fMRI data.

BACKGROUND: Although independent component analysis (ICA) has been widely applied to functional magnetic resonance imaging (fMRI) data to reveal spatially independent brain networks, the order indetermination of ICA leads to the problem of target component selection. The temporally constrained independent component analysis (TCICA) is capable of automatically extracting the desired spatially independent components by adding the temporal prior information of the task to the mixing matrix for fMRI data analysis. However, the TCICA method can only extract a single component that tends to be a mix of multiple task-related components when there exist several independent components related to one task. METHODS: In this study, we proposed a TCICA with threshold (TCICA-Thres) method that performed TCICA outside the threshold and performed FastICA inside the threshold to automatically extract all the target components related to one task. The proposed approach was tested using simulated fMRI data and was applied to a real fMRI experiment using 13 subjects. Additionally, the performance of TCICA-Thres was compared with that of FastICA and TCICA. RESULTS: The results from the simulation and the fMRI data demonstrated that TCICA-Thres better extracted the task-related components than TCICA. Moreover, TCICA-Thres outperformed FastICA in robustness to noise, spatial detection power and computational time. CONCLUSIONS: The proposed TCICA-Thres solves the limitations of TCICA and extends the application of TCICA in fMRI data analysis.

Improved Application of Sparse Representation Classifier in fMRI-based Brain State Decoding.

Multivariate pattern analysis techniques have been widely applied to decode brain states using functional magnetic resonance imaging (fMRI). Among various multivariate pattern analysis methods, sparse representation classifier (SRC) exhibit state-of-the-art classification performance for image classification. However, SRC has rarely been applied to fMRI-based decoding. This study aimed to investigate the feasibility of SRC in fMRI-based decoding and how to improve the performance of SRC. In this study, two SRC variants were proposed to improve SRC. We performed experimental tests on real fMRI data to compare the performance of SRC, the non-negative SRC (NSRC), two SRC variants, and the support vector machine (SVM). The results of the real fMRI experiments showed that the two SRC variants and NSRC exhibited much better classification performance than the SRC. Moreover, the performance of the second SRC variant is the best among the five classifiers.

Brain State Decoding Based on fMRI Using Semisupervised Sparse Representation Classifications.

Multivariate classification techniques have been widely applied to decode brain states using functional magnetic resonance imaging (fMRI). Due to variabilities in fMRI data and the limitation of the collection of human fMRI data, it is not easy to train an efficient and robust supervised-learning classifier for fMRI data. Among various classification techniques, sparse representation classifier (SRC) exhibits a state-of-the-art classification performance in image classification. However, SRC has rarely been applied to fMRI-based decoding. This study aimed to improve SRC using unlabeled testing samples to allow it to be effectively applied to fMRI-based decoding. We proposed a semisupervised-learning SRC with an average coefficient (semiSRC-AVE) method that performed the classification using the average coefficient of each class instead of the reconstruction error and selectively updated the training dataset using new testing data with high confidence to improve the performance of SRC. Simulated and real fMRI experiments were performed to investigate the feasibility and robustness of semiSRC-AVE. The results of the simulated and real fMRI experiments showed that semiSRC-AVE significantly outperformed supervised learning SRC with an average coefficient (SRC-AVE) method and showed better performance than the other three semisupervised learning methods.

Euler Elastica Regularized Logistic Regression for Whole-Brain Decoding of fMRI Data.

OBJECTIVE: Multivariate pattern analysis methods have been widely applied to functional magnetic resonance imaging (fMRI) data to decode brain states. Due to the "high features, low samples" in fMRI data, machine learning methods have been widely regularized using various regularizations to avoid overfitting. Both total variation (TV) using the gradients of images and Euler's elastica (EE) using the gradient and the curvature of images are the two popular regulations with spatial structures. In contrast to TV, EE regulation is able to overcome the disadvantage of TV regulation that favored piecewise constant images over piecewise smooth images. In this study, we introduced EE to fMRI-based decoding for the first time and proposed the EE regularized multinomial logistic regression (EELR) algorithm for multi-class classification. METHODS: We performed experimental tests on both simulated and real fMRI data to investigate the feasibility and robustness of EELR. The performance of EELR was compared with sparse logistic regression (SLR) and TV regularized LR (TVLR). RESULTS: The results showed that EELR was more robustness to noises and showed significantly higher classification performance than TVLR and SLR. Moreover, the forward models and weights patterns revealed that EELR detected larger brain regions that were discriminative to each task and activated by each task than TVLR. CONCLUSION: The results suggest that EELR not only performs well in brain decoding but also reveals meaningful discriminative and activation patterns. SIGNIFICANCE: This study demonstrated that EELR showed promising potential in brain decoding and discriminative/activation pattern detection.

Stereoscopic processing of crossed and uncrossed disparities in the human visual cortex.

BACKGROUND: Binocular disparity provides a powerful cue for depth perception in a stereoscopic environment. Despite increasing knowledge of the cortical areas that process disparity from neuroimaging studies, the neural mechanism underlying disparity sign processing [crossed disparity (CD)/uncrossed disparity (UD)] is still poorly understood. In the present study, functional magnetic resonance imaging (fMRI) was used to explore different neural features that are relevant to disparity-sign processing. METHODS: We performed an fMRI experiment on 27 right-handed healthy human volunteers by using both general linear model (GLM) and multi-voxel pattern analysis (MVPA) methods. First, GLM was used to determine the cortical areas that displayed different responses to different disparity signs. Second, MVPA was used to determine how the cortical areas discriminate different disparity signs. RESULTS: The GLM analysis results indicated that shapes with UD induced significantly stronger activity in the sub-region (LO) of the lateral occipital cortex (LOC) than those with CD. The results of MVPA based on region of interest indicated that areas V3d and V3A displayed higher accuracy in the discrimination of crossed and uncrossed disparities than LOC. The results of searchlight-based MVPA indicated that the dorsal visual cortex showed significantly higher prediction accuracy than the ventral visual cortex and the sub-region LO of LOC showed high accuracy in the discrimination of crossed and uncrossed disparities. CONCLUSIONS: The results may suggest the dorsal visual areas are more discriminative to the disparity signs than the ventral visual areas although they are not sensitive to the disparity sign processing. Moreover, the LO in the ventral visual cortex is relevant to the recognition of shapes with different disparity signs and discriminative to the disparity sign.

Prediction of Progressive Mild Cognitive Impairment by Multi-Modal Neuroimaging Biomarkers.

For patients with mild cognitive impairment (MCI), the likelihood of progression to probable Alzheimer's disease (AD) is important not only for individual patient care, but also for the identification of participants in clinical trial, so as to provide early interventions. Biomarkers based on various neuroimaging modalities could offer complementary information regarding different aspects of disease progression. The current study adopted a weighted multi-modality sparse representation-based classification method to combine data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, from three imaging modalities: Volumetric magnetic resonance imaging (MRI), fluorodeoxyglucose (FDG) positron emission tomography (PET), and florbetapir PET. We included 117 normal controls (NC) and 110 MCI patients, 27 of whom progressed to AD within 36 months (pMCI), while the remaining 83 remained stable (sMCI) over the same time period. Modality-specific biomarkers were identified to distinguish MCI from NC and to predict pMCI among MCI. These included the hippocampus, amygdala, middle temporal and inferior temporal regions for MRI, the posterior cingulum, precentral, and postcentral regions for FDG-PET, and the hippocampus, amygdala, and putamen for florbetapir PET. Results indicated that FDG-PET may be a more effective modality in discriminating MCI from NC and in predicting pMCI than florbetapir PET and MRI. Combining modality-specific sensitive biomarkers from the three modalities boosted the discrimination accuracy of MCI from NC (76.7%) and the prediction accuracy of pMCI (82.5%) when compared with the best single-modality results (73.6% for MCI and 75.6% for pMCI with FDG-PET).

Improved FastICA algorithm in fMRI data analysis using the sparsity property of the sources.

BACKGROUND: As a blind source separation technique, independent component analysis (ICA) has many applications in functional magnetic resonance imaging (fMRI). Although either temporal or spatial prior information has been introduced into the constrained ICA and semi-blind ICA methods to improve the performance of ICA in fMRI data analysis, certain types of additional prior information, such as the sparsity, has seldom been added to the ICA algorithms as constraints. NEW METHOD: In this study, we proposed a SparseFastICA method by adding the source sparsity as a constraint to the FastICA algorithm to improve the performance of the widely used FastICA. The source sparsity is estimated through a smoothed ℓ0 norm method. We performed experimental tests on both simulated data and real fMRI data to investigate the feasibility and robustness of SparseFastICA and made a performance comparison between SparseFastICA, FastICA and Infomax ICA. RESULTS: Results of the simulated and real fMRI data demonstrated the feasibility and robustness of SparseFastICA for the source separation in fMRI data. COMPARISON WITH EXISTING METHODS: Both the simulated and real fMRI experimental results showed that SparseFastICA has better robustness to noise and better spatial detection power than FastICA. Although the spatial detection power of SparseFastICA and Infomax did not show significant difference, SparseFastICA had faster computation speed than Infomax. CONCLUSIONS: SparseFastICA was comparable to the Infomax algorithm with a faster computation speed. More importantly, SparseFastICA outperformed FastICA in robustness and spatial detection power and can be used to identify more accurate brain networks than FastICA algorithm.

Meta-analysis of real-time fMRI neurofeedback studies using individual participant data: How is brain regulation mediated?

An increasing number of studies using real-time fMRI neurofeedback have demonstrated that successful regulation of neural activity is possible in various brain regions. Since these studies focused on the regulated region(s), little is known about the target-independent mechanisms associated with neurofeedback-guided control of brain activation, i.e. the regulating network. While the specificity of the activation during self-regulation is an important factor, no study has effectively determined the network involved in self-regulation in general. In an effort to detect regions that are responsible for the act of brain regulation, we performed a post-hoc analysis of data involving different target regions based on studies from different research groups. We included twelve suitable studies that examined nine different target regions amounting to a total of 175 subjects and 899 neurofeedback runs. Data analysis included a standard first- (single subject, extracting main paradigm) and second-level (single subject, all runs) general linear model (GLM) analysis of all participants taking into account the individual timing. Subsequently, at the third level, a random effects model GLM included all subjects of all studies, resulting in an overall mixed effects model. Since four of the twelve studies had a reduced field of view (FoV), we repeated the same analysis in a subsample of eight studies that had a well-overlapping FoV to obtain a more global picture of self-regulation. The GLM analysis revealed that the anterior insula as well as the basal ganglia, notably the striatum, were consistently active during the regulation of brain activation across the studies. The anterior insula has been implicated in interoceptive awareness of the body and cognitive control. Basal ganglia are involved in procedural learning, visuomotor integration and other higher cognitive processes including motivation. The larger FoV analysis yielded additional activations in the anterior cingulate cortex, the dorsolateral and ventrolateral prefrontal cortex, the temporo-parietal area and the visual association areas including the temporo-occipital junction. In conclusion, we demonstrate that several key regions, such as the anterior insula and the basal ganglia, are consistently activated during self-regulation in real-time fMRI neurofeedback independent of the targeted region-of-interest. Our results imply that if the real-time fMRI neurofeedback studies target regions of this regulation network, such as the anterior insula, care should be given whether activation changes are related to successful regulation, or related to the regulation process per se. Furthermore, future research is needed to determine how activation within this regulation network is related to neurofeedback success.