Microglial Imaging in Alzheimer's Disease and Its Relationship to Brain Amyloid: A Human 18F-GE180 PET Study.

BACKGROUND: Emerging evidence suggests a potential causal role of neuroinflammation in Alzheimer's disease (AD). Using positron emission tomography (PET) to image overexpressed 18 kDA translocator protein (TSPO) by activated microglia has gained increasing interest. The uptake of 18F-GE180 TSPO PET was observed to co-localize with inflammatory markers and have a two-stage association with amyloid PET in mice. Very few studies evaluated the diagnostic power of 18F-GE180 PET in AD population and its interpretation in human remains controversial about whether it is a marker of microglial activation or merely reflects disrupted blood-brain barrier integrity in humans. OBJECTIVE: The goal of this study was to study human GE180 from the perspective of the previous animal observations. METHODS: With data from twenty-four participants having 18F-GE180 and 18F-AV45 PET scans, we evaluated the group differences of 18F-GE180 uptake between participants with and without cognitive impairment. An association analysis of 18F-GE180 and 18F-AV45 was then conducted to test if the relationship in humans is consistent with the two-stage association in AD mouse model. RESULTS: Elevated 18F-GE180 was observed in participants with cognitive impairment compared to those with normal cognition. No regions showed reduced 18F-GE180 uptake. Consistent with mouse model, a two-stage association between 18F-GE180 and 18F-AV45 was observed. CONCLUSIONS: 18F-GE180 PET imaging showed promising utility in detecting pathological alterations in a symptomatic AD population. Consistent two-stage association between 18F-GE180 and amyloid PET in human and mouse suggested that 18F-GE180 uptake in human might be considerably influenced by microglial activation.

Clinical and biological relevance of glial fibrillary acidic protein in Alzheimer's disease.

INTRODUCTION: There is a tremendous need for identifying reliable blood-based biomarkers for Alzheimer's disease (AD) that are tied to the biological ATN (amyloid, tau and neurodegeneration) framework as well as clinical assessment and progression. METHODS: One hundred forty-four elderly participants underwent 18F-AV45 positron emission tomography (PET) scan, structural magnetic resonance imaging (MRI) scan, and blood sample collection. The composite standardized uptake value ratio (SUVR) was derived from 18F-AV45 PET to assess brain amyloid burden, and the hippocampal volume was determined from structural MRI scans. Plasma glial fibrillary acidic protein (GFAP), phosphorylated tau-181 (ptau-181), and neurofilament light (NfL) measured by single molecular array (SIMOA) technology were assessed with respect to ATN framework, genetic risk factor, age, clinical assessment, and future functional decline among the participants. RESULTS: Among the three plasma markers, GFAP best discriminated participants stratified by clinical diagnosis and brain amyloid status. Age was strongly associated with NfL, followed by GFAP and ptau-181 at much weaker extent. Brain amyloid was strongly associated with plasma GFAP and ptau-181 and to a lesser extent with plasma NfL. Moderate association was observed between plasma markers. Hippocampal volume was weakly associated with all three markers. Elevated GFAP and ptau-181 were associated with worse cognition, and plasma GFAP was the most predictive of future functional decline. Combining GFAP and ptau-181 together was the best model to predict brain amyloid status across all participants (AUC = 0.86) or within cognitively impaired participants (AUC = 0.93); adding NfL as an additional predictor only had a marginal improvement. CONCLUSION: Our findings indicate that GFAP is of potential clinical utility in screening amyloid pathology and predicting future cognitive decline. GFAP, NfL, and ptau-181 were moderately associated with each other, with discrepant relevance to age, sex, and AD genetic risk, suggesting their relevant but differential roles for AD assessment. The combination of GFAP with ptau-181 provides an accurate model to predict brain amyloid status, with the superior performance of GFAP over ptau-181 when the prediction is limited to cognitively impaired participants.

Cortical thickness is related to cognitive-motor automaticity and attention allocation in individuals with Alzheimer's disease: a regions of interest study.

Alzheimer's disease (AD) is characterized by a distinct pattern of cortical thinning and resultant changes in cognition and function. These result in prominent deficits in cognitive-motor automaticity. The relationship between AD-related cortical thinning and decreased automaticity is not well-understood. We aimed to investigate the relationship between cortical thickness regions-of-interest (ROI) and automaticity and attention allocation in AD using hypothesis-driven and exploratory approaches. We performed an ROI analysis of 46 patients with AD. Data regarding MR images, demographic characteristics, cognitive-motor dual task performance, and cognition were extracted from medical records. Cortical thickness was calculated from MR T1 images using FreeSurfer. Data from the dual task assessment was used to calculate the combined dual task effect (cDTE), a measure of cognitive-motor automaticity, and the modified attention allocation index (mAAI). Four hierarchical multiple linear regression models were conducted regressing cDTE and mAAI separately on (1) hypothesis-generated ROIs and (2) exploratory ROIs. For cDTE, cortical thicknesses explained 20.5% (p = 0.014) and 25.9% (p = 0.002) variability in automaticity in the hypothesized ROI and exploratory models, respectively. The dorsal lateral prefrontal cortex (DLPFC) (ß = - 0.479, p = 0.018) and superior parietal cortex (SPC) (ß = 0.467, p = 0.003), and were predictors of automaticity. For mAAI, cortical thicknesses explained 20.7% (p = 0.025) and 28.3% (p = 0.003) variability in attention allocation in the hypothesized ROI and exploratory models, respectively. Thinning of SPC and fusiform gyrus were associated with motor prioritization (ß = - 0.405, p = 0.013 and ß = - 0.632, p = 0.004, respectively), whereas thinning of the DLPFC was associated with cognitive prioritization (ß = 0.523, p = 0.022). Cortical thinning in AD was related to cognitive-motor automaticity and task prioritization, particularly in the DLPFC and SPC. This suggests that these regions may play a primary role in automaticity and attentional strategy during dual-tasking.

Topological reorganization of functional hubs in patients with Parkinson's disease with freezing of gait.

BACKGROUND AND PURPOSE: Resting-state functional MRI (rs-fMRI) studies in Parkinson's disease (PD) patients with freezing of gait (FOG) have implicated dysfunctional connectivity over multiple resting-state networks (RSNs). While these findings provided network-specific insights and information related to the aberrant or altered regional functional connectivity (FC), whether these alterations have any effect on topological reorganization in PD-FOG patients is incompletely understood. Understanding the higher order functional organization, which could be derived from the "hub" and the "rich-club" organization of the functional networks, could be crucial to identifying the distinct and unique pattern of the network connectivity associated with PD-FOG. METHODS: In this study, we use rs-fMRI data and graph theoretical approaches to explore the reorganization of RSN topology in PD-FOG when compared to those without FOG. We also compared the higher order functional organization derived using the hub and rich-club measures in the FC networks of these PD-FOG patients to understand whether there is a topological reorganization of these hubs in PD-FOG. RESULTS: We found that the PD-FOG patients showed a noticeable reorganization of hub regions. Regions that are part of the prefrontal cortex, primary somatosensory, motor, and visuomotor coordination areas were some of the regions exhibiting altered hub measures in PD-FOG patients. We also found a significantly altered feeder and local connectivity in PD-FOG. CONCLUSIONS: Overall, our findings demonstrate a widespread topological reorganization and disrupted higher order functional network topology in PD-FOG that may further assist in improving our understanding of functional network disturbances associated with PD-FOG.

Energy-Period Profiles of Brain Networks in Group fMRI Resting-State Data: A Comparison of Empirical Mode Decomposition With the Short-Time Fourier Transform and the Discrete Wavelet Transform.

Traditionally, functional networks in resting-state data were investigated with linear Fourier and wavelet-related methods to characterize their frequency content by relying on pre-specified frequency bands. In this study, Empirical Mode Decomposition (EMD), an adaptive time-frequency method, is used to investigate the naturally occurring frequency bands of resting-state data obtained by Group Independent Component Analysis. Specifically, energy-period profiles of Intrinsic Mode Functions (IMFs) obtained by EMD are created and compared for different resting-state networks. These profiles have a characteristic distribution for many resting-state networks and are related to the frequency content of each network. A comparison with the linear Short-Time Fourier Transform (STFT) and the Maximal Overlap Discrete Wavelet Transform (MODWT) shows that EMD provides a more frequency-adaptive representation of different types of resting-state networks. Clustering of resting-state networks based on the energy-period profiles leads to clusters of resting-state networks that have a monotone relationship with frequency and energy. This relationship is strongest with EMD, intermediate with MODWT, and weakest with STFT. The identification of these relationships suggests that EMD has significant advantages in characterizing brain networks compared to STFT and MODWT. In a clinical application to early Parkinson's disease (PD) vs. normal controls (NC), energy and period content were studied for several common resting-state networks. Compared to STFT and MODWT, EMD showed the largest differences in energy and period between PD and NC subjects. Using a support vector machine, EMD achieved the highest prediction accuracy in classifying NC and PD subjects among STFT, MODWT, and EMD.

Resting-State Static and Dynamic Functional Abnormalities in Active Professional Fighters With Repetitive Head Trauma and With Neuropsychological Impairments.

Previous neuroimaging studies have identified structural brain abnormalities in active professional fighters with repetitive head trauma and correlated these changes with fighters' neuropsychological impairments. However, functional brain changes in these fighters derived using neuroimaging techniques remain unclear. In this study, both static and dynamic functional connectivity alterations were investigated (1) between healthy normal control subjects (NC) and fighters and (2) between non-impaired and impaired fighters. Resting-state fMRI data were collected on 35 NC and 133 active professional fighters, including 68 impaired fighters and 65 non-impaired fighters, from the Professional Fighters Brain Health Study at our center. Impaired fighters performed worse on processing speed (PSS) tasks with visual-attention and working-memory demands. The static functional connectivity (sFC) matrix was estimated for every pair of regions of interest (ROI) using a subject-specific parcellation. The dynamic functional connectivity (dFC) was estimated using a sliding-window method, where the variability of each ROI pair across all windows represented the temporal dynamics. A linear regression model was fitted for all 168 subjects, and different t-contrast vectors were used for between-group comparisons. An association analysis was further conducted to evaluate FC changes associated with PSS task performances without creating artificial impairment group-divisions in fighters. Following corrections for multiple comparisons using network-based statistics, our study identified significantly reduced long-range frontal-temporal, frontal-occipital, temporal-occipital, and parietal-occipital sFC strengths in fighters than in NCs, corroborating with previously observed structural damages in corresponding white matter tracts in subjects experiencing repetitive head trauma. In impaired fighters, significantly decreased sFC strengths were found among key regions involved in visual-attention, executive and cognitive process, as compared to non-impaired fighters. Association analysis further reveals similar sFC deficits to worse PSS task performances in all 133 fighters. With our choice of dFC indices, we were not able to observe any significant dFC changes beyond a trend-level increased temporal variability among similar regions with weaker sFC strengths in impaired fighters. Collectively, our functional brain findings supplement previously reported structural brain abnormalities in fighters and are important to comprehensively understand brain changes in fighters with repetitive head trauma.

Disentangling time series between brain tissues improves fMRI data quality using a time-dependent deep neural network.

Functional MRI (fMRI) is a prominent imaging technique to probe brain function, however, a substantial proportion of noise from multiple sources influences the reliability and reproducibility of fMRI data analysis and limits its clinical applications. Extensive effort has been devoted to improving fMRI data quality, but in the last two decades, there is no consensus reached which technique is more effective. In this study, we developed a novel deep neural network for denoising fMRI data, named denoising neural network (DeNN). This deep neural network is 1) applicable without requiring externally recorded data to model noise; 2) spatially and temporally adaptive to the variability of noise in different brain regions at different time points; 3) automated to output denoised data without manual interference; 4) trained and applied on each subject separately and 5) insensitive to the repetition time (TR) of fMRI data. When we compared DeNN with a number of nuisance regression methods for denoising fMRI data from Alzheimer's Disease Neuroimaging Initiative (ADNI) database, only DeNN had connectivity for functionally uncorrelated regions close to zero and successfully identified unbiased correlations between the posterior cingulate cortex seed and multiple brain regions within the default mode network or task positive network. The whole brain functional connectivity maps computed with DeNN-denoised data are approximately three times as homogeneous as the functional connectivity maps computed with raw data. Furthermore, the improved homogeneity strengthens rather than weakens the statistical power of fMRI in detecting intrinsic functional differences between cognitively normal subjects and subjects with Alzheimer's disease.

Single-scale time-dependent window-sizes in sliding-window dynamic functional connectivity analysis: A validation study.

During the past ten years, dynamic functional connectivity (FC) has been extensively studied using the sliding-window method. A fixed window-size is usually selected heuristically, since no consensus exists yet on choice of the optimal window-size. Furthermore, without a known ground-truth, the validity of the computed dynamic FC remains unclear and questionable. In this study, we computed single-scale time-dependent (SSTD) window-sizes for the sliding-window method. SSTD window-sizes were based on the frequency content at every time point of a time series and were computed without any prior information. Therefore, they were time-dependent and data-driven. Using simulated sinusoidal time series with frequency shifts, we demonstrated that SSTD window-sizes captured the time-dependent period (inverse of frequency) information at every time point. We further validated the dynamic FC values computed with SSTD window-sizes with both a classification analysis using fMRI data with a low sampling rate and a regression analysis using fMRI data with a high sampling rate. Specifically, we achieved both a higher classification accuracy in predicting cognitive impairment status in fighters and a larger explained behavioral variance in healthy young adults when using dynamic FC matrices computed with SSTD window-sizes as features, as compared to using dynamic FC matrices computed with the conventional fixed window-sizes. Overall, our study computed and validated SSTD window-sizes in the sliding-window method for dynamic FC analysis. Our results demonstrate that dynamic FC matrices computed with SSTD window-sizes can capture more temporal dynamic information related to behavior and cognitive function.

CAST: A multi-scale convolutional neural network based automated hippocampal subfield segmentation toolbox.

In this study, we developed a multi-scale Convolutional neural network based Automated hippocampal subfield Segmentation Toolbox (CAST) for automated segmentation of hippocampal subfields. Although training CAST required approximately three days on a single workstation with a high-quality GPU card, CAST can segment a new subject in less than 1 â€‹min even with GPU acceleration disabled, thus this method is more time efficient than current automated methods and manual segmentation. This toolbox is highly flexible with either a single modality or multiple modalities and can be easily set up to be trained with a researcher's unique data. A 3D multi-scale deep convolutional neural network is the key algorithm used in the toolbox. The main merit of multi-scale images is the capability to capture more global structural information from down-sampled images without dramatically increasing memory and computational burden. The original images capture more local information to refine the boundary between subfields. Residual learning is applied to alleviate the vanishing gradient problem and improve the performance with a deeper network. We applied CAST with the same settings on two datasets, one 7T dataset (the UMC dataset) with only the T2 image and one 3T dataset (the MNI dataset) with both T1 and T2 images available. The segmentation accuracy of both CAST and the state-of-the-art automated method ASHS, in terms of the dice similarity coefficient (DSC), were comparable. CAST significantly improved the reliability of segmenting small subfields, such as CA2, CA3, and the entorhinal cortex (ERC), in terms of the intraclass correlation coefficient (ICC). Both ASHS and manual segmentation process some subfields (e.g. CA2 and ERC) with high DSC values but low ICC values, consequently increasing the difficulty of judging segmentation quality. CAST produces very consistent DSC and ICC values, with a maximal discrepancy of 0.01 (DSC-ICC) across all subfields. The pre-trained model, source code, and settings for the CAST toolbox are publicly available.

Unique white matter structural connectivity in early-stage drug-naive Parkinson disease.

OBJECTIVE: To investigate the topographic arrangement and strength of whole-brain white matter (WM) structural connectivity in patients with early-stage drug-naive Parkinson disease (PD). METHODS: We employed a model-free data-driven approach for computing whole-brain WM topologic arrangement and connectivity strength between brain regions by utilizing diffusion MRI of 70 participants with early-stage drug-naive PD and 41 healthy controls. Subsequently, we generated a novel group-specific WM anatomical network by minimizing variance in anatomical connectivity of each group. Global WM connectivity strength and network measures were computed on this group-specific WM anatomical network and were compared between the groups. We tested correlations of these network measures with clinical measures in PD to assess their pathophysiologic relevance. RESULTS: PD-relevant cortical and subcortical regions were identified in the novel PD-specific WM anatomical network. Impaired modular organization accompanied by a correlation of network measures with multiple clinical variables in early PD were revealed. Furthermore, disease duration was negatively correlated with global connectivity strength of the PD-specific WM anatomical network. CONCLUSION: By minimizing variance in anatomical connectivity, this study found the presence of a novel WM structural connectome in early PD that correlated with clinical symptoms, despite the lack of a priori analytic assumptions. This included the novel finding of increased structural connectivity between known PD-relevant brain regions. The current study provides a framework for further investigation of WM structural changes underlying the clinical and pathologic heterogeneity of PD.

A robust deep neural network for denoising task-based fMRI data: An application to working memory and episodic memory.

In this study, a deep neural network (DNN) is proposed to reduce the noise in task-based fMRI data without explicitly modeling noise. The DNN artificial neural network consists of one temporal convolutional layer, one long short-term memory (LSTM) layer, one time-distributed fully-connected layer, and one unconventional selection layer in sequential order. The LSTM layer takes not only the current time point but also what was perceived in a previous time point as its input to characterize the temporal autocorrelation of fMRI data. The fully-connected layer weights the output of the LSTM layer, and the output denoised fMRI time series is selected by the selection layer. Assuming that task-related neural response is limited to gray matter, the model parameters in the DNN network are optimized by maximizing the correlation difference between gray matter voxels and white matter or ventricular cerebrospinal fluid voxels. Instead of targeting a particular noise source, the proposed neural network takes advantage of the task design matrix to better extract task-related signal in fMRI data. The DNN network, along with other traditional denoising techniques, has been applied on simulated data, working memory task fMRI data acquired from a cohort of healthy subjects and episodic memory task fMRI data acquired from a small set of healthy elderly subjects. Qualitative and quantitative measurements were used to evaluate the performance of different denoising techniques. In the simulation, DNN improves fMRI activation detection and also adapts to varying hemodynamic response functions across different brain regions. DNN efficiently reduces physiological noise and generates more homogeneous task-response correlation maps in real data.

Understanding white matter structural connectivity differences between cognitively impaired and nonimpaired active professional fighters.

Long-term traumatic brain injury due to repeated head impacts (RHI) has been shown to be a risk factor for neurodegenerative disorders, characterized by a loss in cognitive performance. Establishing the correlation between changes in the white matter (WM) structural connectivity measures and neuropsychological test scores might help to identify the neural correlates of the scores that are used in daily clinical setting to investigate deficits due to repeated head blows. Hence, in this study, we utilized high angular diffusion MRI (dMRI) of 69 cognitively impaired and 70 nonimpaired active professional fighters from the Professional Fighters Brain Health Study, and constructed structural connectomes to understand: (a) whether there is a difference in the topological WM organization between cognitively impaired and nonimpaired active professional fighters, and (b) whether graph-theoretical measures exhibit correlations with neuropsychological scores in these groups. A dMRI derived structural connectome was constructed for every participant using brain regions defined in AAL atlas as nodes, and the product of fiber number and average fractional anisotropy of the tracts connecting the nodes as edges. Our study identified a topological WM reorganization due to RHI in fighters prone to cognitive decline that was correlated with neuropsychological scores. Furthermore, graph-theoretical measures were correlated differentially with neuropsychological scores between groups. We also found differentiated WM connectivity involving regions of hippocampus, precuneus, and insula within our cohort of cognitively impaired fighters suggesting that there is a discernible WM topological reorganization in fighters prone to cognitive decline.

Performing Sparse Regularization and Dimension Reduction Simultaneously in Multimodal Data Fusion.

Collecting multiple modalities of neuroimaging data on the same subject is increasingly becoming the norm in clinical practice and research. Fusing multiple modalities to find related patterns is a challenge in neuroimaging analysis. Canonical correlation analysis (CCA) is commonly used as a symmetric data fusion technique to find related patterns among multiple modalities. In CCA-based data fusion, principal component analysis (PCA) is frequently applied as a preprocessing step to reduce data dimension followed by CCA on dimension-reduced data. PCA, however, does not differentiate between informative voxels from non-informative voxels in the dimension reduction step. Sparse PCA (sPCA) extends traditional PCA by adding sparse regularization that assigns zero weights to non-informative voxels. In this study, sPCA is incorporated into CCA-based fusion analysis and applied on neuroimaging data. A cross-validation method is developed and validated to optimize the parameters in sPCA. Different simulations are carried out to evaluate the improvement by introducing sparsity constraint to PCA. Four fusion methods including sPCA+CCA, PCA+CCA, parallel ICA and sparse CCA were applied on structural and functional magnetic resonance imaging data of mild cognitive impairment subjects and normal controls. Our results indicate that sPCA significantly can reduce the impact of non-informative voxels and lead to improved statistical power in uncovering disease-related patterns by a fusion analysis.

Robust Motion Regression of Resting-State Data Using a Convolutional Neural Network Model.

Resting-state functional magnetic resonance imaging (rs-fMRI) based on the blood-oxygen-level-dependent (BOLD) signal has been widely used in healthy individuals and patients to investigate brain functions when the subjects are in a resting or task-negative state. Head motion considerably confounds the interpretation of rs-fMRI data. Nuisance regression is commonly used to reduce motion-related artifacts with six motion parameters estimated from rigid-body realignment as regressors. To further compensate for the effect of head movement, the first-order temporal derivatives of motion parameters and squared motion parameters were proposed previously as possible motion regressors. However, these additional regressors may not be sufficient to model the impact of head motion because of the complexity of motion artifacts. In addition, while using more motion-related regressors could explain more variance in the data, the neural signal may also be removed with increasing number of motion regressors. To better model how in-scanner motion affects rs-fMRI data, a robust and automated convolutional neural network (CNN) model is developed in this study to obtain optimal motion regressors. The CNN network consists of two temporal convolutional layers and the output from the network are the derived motion regressors used in the following nuisance regression. The temporal convolutional layer in the network can non-parametrically model the prolonged effect of head motion. The set of regressors derived from the neural network is compared with the same number of regressors used in a traditional nuisance regression approach. It is demonstrated that the CNN-derived regressors can more effectively reduce motion-related artifacts.

Influence of analytic techniques on comparing DTI-derived measurements in early stage Parkinson's disease.

Diffusion tensor imaging (DTI) studies in early Parkinson's disease (PD) to understand pathologic changes in white matter (WM) organization are variable in their findings. Evaluation of different analytic techniques frequently employed to understand the DTI-derived change in WM organization in a multisite, well-characterized, early stage PD cohort should aid the identification of the most robust analytic techniques to be used to investigate WM pathology in this disease, an important unmet need in the field. Thus, region of interest (ROI)-based analysis, voxel-based morphometry (VBM) analysis with varying spatial smoothing, and the two most widely used skeletonwise approaches (tract-based spatial statistics, TBSS, and tensor-based registration, DTI-TK) were evaluated in a DTI dataset of early PD and Healthy Controls (HC) from the Parkinson's Progression Markers Initiative (PPMI) cohort. Statistical tests on the DTI-derived metrics were conducted using a nonparametric approach from this cohort of early PD, after rigorously controlling for motion and signal artifacts during DTI scan which are frequent confounds in this disease population. Both TBSS and DTI-TK revealed a significantly negative correlation of fractional anisotropy (FA) with disease duration. However, only DTI-TK revealed radial diffusivity (RD) to be driving this FA correlation with disease duration. HC had a significantly positive correlation of MD with cumulative DaT score in the right middle-frontal cortex after a minimum smoothing level (at least 13mm) was attained. The present study found that scalar DTI-derived measures such as FA, MD, and RD should be used as imaging biomarkers with caution in early PD as the conclusions derived from them are heavily dependent on the choice of the analysis used. This study further demonstrated DTI-TK may be used to understand changes in DTI-derived measures with disease progression as it was found to be more accurate than TBSS. In addition, no singular region was identified that could explain both disease duration and severity in early PD. The results of this study should help standardize the utilization of DTI-derived measures in PD in an effort to improve comparability across studies and time, and to minimize variability in reported results due to variation in techniques.

Multivariate group-level analysis for task fMRI data with canonical correlation analysis.

Task-based functional Magnetic Resonance Imaging (fMRI) has been widely used to determine population-based brain activations for cognitive tasks. Popular group-level analysis in fMRI is based on the general linear model and constitutes a univariate method. However, univariate methods are known to suffer from low sensitivity for a given specificity because the spatial covariance structure at each voxel is not taken entirely into account. In this study, a spatially constrained local multivariate model is introduced for group-level analysis to improve sensitivity at a given specificity for activation detection. The proposed model is formulated in terms of a multivariate constrained optimization problem based on the maximum log likelihood method and solved efficiently with numerical optimization techniques. Both simulated data mimicking real fMRI time series at multiple noise fractions and real fMRI episodic memory data have been used to evaluate the performance of the proposed method. For simulated data, the area under the receiver operating characteristic curves in detecting group activations increases for the subject and group level multivariate method by 20%, as compared to the univariate method. Results from real fMRI data indicate a significant increase in group-level activation detection, particularly in hippocampus, para-hippocampal area and nearby medial temporal lobe regions with the proposed method.

Altered functional network topology correlates with clinical measures in very early-stage, drug-naïve Parkinson's disease.

INTRODUCTION: The aim of the study was to identify abnormalities of whole-brain network functional organization and their relation to clinical measures in a well-characterized, multi-site cohort of very early-stage, drug-naïve Parkinson's Disease (PD) patients. METHODS: Functional-MRI data for 16 healthy controls and 20 very early-stage, drug-naïve patients with PD were obtained from the Parkinson's Progression Markers Initiative database after controlling for strict inclusion/exclusion imaging criteria. Connectivity between regions of interest was estimated using Pearson's correlation between averaged time-series, and subsequently a connectivity matrix was obtained for each subject. These connectivity matrices were then used in an unbiased, whole-brain graph theoretical approach to investigate the functional connectome and its correlation with disease severity in very early PD. RESULTS: The current study revealed altered network topology which correlated with multiple clinical measures in very early drug-naïve PD. Decreased functional segregation and integration (both globally and locally) were evident in PD. Importantly, our results demonstrated that most of the cortical regions hypothesized to be involved early in PD manifested decreased graph theoretical measures, despite utilizing a whole-brain analytic approach that is free from prior assumptions regarding cortical region involvement. CONCLUSION: Graph theoretical investigation of very early drug-naïve PD revealed disrupted topological organization. These findings are evident in a stringently homogeneous group of very early-stage, medication-naive, and non-tremor dominant PD patients by using a whole-brain unbiased approach. These results provide an important unbiased and rigorously controlled baseline for understanding further studies of PD functional connectivity investigating response to treatment, symptom development, and disease progression.

Advances in functional magnetic resonance imaging data analysis methods using Empirical Mode Decomposition to investigate temporal changes in early Parkinson's disease.

INTRODUCTION: Previous neuroimaging studies of Parkinson's disease (PD) patients have shown changes in whole-brain functional connectivity networks. Whether connectivity changes can be detected in the early stages (first 3 years) of PD by resting-state functional magnetic resonance imaging (fMRI) remains elusive. Research infrastructure including MRI and analytic capabilities is required to investigate this issue. The National Institutes of Health/National Institute of General Medical Sciences Center for Biomedical Research Excellence awards support infrastructure to advance research goals. METHODS: Static and dynamic functional connectivity analyses were conducted on early stage never-medicated PD subjects (N = 18) and matched healthy controls (N = 18) from the Parkinson's Progression Markers Initiative. RESULTS: Altered static and altered dynamic functional connectivity patterns were found in early PD resting-state fMRI data. Most static networks (with the exception of the default mode network) had a reduction in frequency and energy in specific low-frequency bands. Changes in dynamic networks in PD were associated with a decreased switching rate of brain states. DISCUSSION: This study demonstrates that in early PD, resting-state fMRI networks show spatial and temporal differences of fMRI signal characteristics. However, the default mode network was not associated with any measurable changes. Furthermore, by incorporating an optimum window size in a dynamic functional connectivity analysis, we found altered whole-brain temporal features in early PD, showing that PD subjects spend significantly more time than healthy controls in a specific brain state. These findings may help in improving diagnosis of early never-medicated PD patients. These key observations emerged in a Center for Biomedical Research Excellence-supported research environment.

Incorporating spatial constraint in co-activation pattern analysis to explore the dynamics of resting-state networks: An application to Parkinson's disease.

The dynamics of the brain's intrinsic networks have been recently studied using co-activation pattern (CAP) analysis. The CAP method relies on few model assumptions and CAP-based measurements provide quantitative information of network temporal dynamics. One limitation of existing CAP-related methods is that the computed CAPs share considerable spatial overlap that may or may not be functionally distinct relative to specific network dynamics. To more accurately describe network dynamics with spatially distinct CAPs, and to compare network dynamics between different populations, a novel data-driven CAP group analysis method is proposed in this study. In the proposed method, a dominant-CAP (d-CAP) set is synthesized across CAPs from multiple clustering runs for each group with the constraint of low spatial similarities among d-CAPs. Alternating d-CAPs with less overlapping spatial patterns can better capture overall network dynamics. The number of d-CAPs, the temporal fraction and spatial consistency of each d-CAP, and the subject-specific switching probability among all d-CAPs are then calculated for each group and used to compare network dynamics between groups. The spatial dissimilarities among d-CAPs computed with the proposed method were first demonstrated using simulated data. High consistency between simulated ground-truth and computed d-CAPs was achieved, and detailed comparisons between the proposed method and existing CAP-based methods were conducted using simulated data. In an effort to physiologically validate the proposed technique and investigate network dynamics in a relevant brain network disorder, the proposed method was then applied to data from the Parkinson's Progression Markers Initiative (PPMI) database to compare the network dynamics in Parkinson's disease (PD) and normal control (NC) groups. Fewer d-CAPs, skewed distribution of temporal fractions of d-CAPs, and reduced switching probabilities among final d-CAPs were found in most networks in the PD group, as compared to the NC group. Furthermore, an overall negative association between switching probability among d-CAPs and disease severity was observed in most networks in the PD group as well. These results expand upon previous findings from in vivo electrophysiological recording studies in PD. Importantly, this novel analysis also demonstrates that changes in network dynamics can be measured using resting-state fMRI data from subjects with early stage PD.

Investigating structural and perfusion deficits due to repeated head trauma in active professional fighters.

Repeated head trauma experienced by active professional fighters results in various structural, functional and perfusion damage. However, whether there are common regions of structural and perfusion damage due to fighting and whether these structural and perfusion differences are associated with neuropsychological measurements in active professional fighters is still unknown. To that end, T1-weighted and pseudocontinuous arterial spin labeling MRI on a group of healthy controls and active professional fighters were acquired. Voxelwise group comparisons, in a univariate and multivariate sense, were performed to investigate differences in gray and white matter density (GMD, WMD) and cerebral blood flow (CBF) between the two groups. A significantly positive association between global GMD and WMD was obtained with psychomotor speed and reaction time, respectively, in our cohort of active professional fighters. In addition, regional WMD deficit was observed in a cluster encompassing bilateral pons, hippocampus, and thalamus in fighters (0.49 ± 0.04 arbitrary units (a.u.)) as compared to controls (0.51 ± 0.05a.u.). WMD in the cluster of active fighters was also significantly associated with reaction time. Significantly lower CBF was observed in right inferior temporal lobe with both partial volume corrected (46.9 ± 14.93 ml/100 g/min) and non-partial volume corrected CBF maps (25.91 ± 7.99 ml/100 g/min) in professional fighters, as compared to controls (65.45 ± 22.24 ml/100 g/min and 35.22 ± 12.18 ml/100 g/min respectively). A paradoxical increase in CBF accompanying right cerebellum and fusiform gyrus in the active professional fighters (29.52 ± 13.03 ml/100 g/min) as compared to controls (19.43 ± 12.56 ml/100 g/min) was observed with non-partial volume corrected CBF maps. Multivariate analysis with both structural and perfusion measurements found the same clusters as univariate analysis in addition to a cluster in right precuneus. Both partial volume corrected and non-partial volume corrected CBF of the cluster in the thalamus had a significantly positive association with the number of fights. In addition, GMD of the cluster in right precuneus was significantly associated with psychomotor speed in our cohort of active professional fighters. Our results suggest a heterogeneous pattern of structural and CBF deficits due to repeated head trauma in active professional fighters. This finding indicates that investigating both structural and CBF changes in the same set of participants may help to understand the pathophysiology and progression of cognitive decline due to repeated head trauma.