Interpreting Age Effects of Human Fetal Brain from Spontaneous fMRI using Deep 3D Convolutional Neural Networks

Understanding human fetal neurodevelopment is of great clinical importance as abnormal development is linked to adverse neuropsychiatric outcomes after birth. Recent advances in functional Magnetic Resonance Imaging (fMRI) have provided new insight into development of the human brain before birth, but these studies have predominately focused on brain functional connectivity (i.e. Fisher z-score), which requires manual processing steps for feature extraction from fMRI images. Deep learning approaches (i.e., Convolutional Neural Networks) have achieved remarkable success on learning directly from image data, yet have not been applied on fetal fMRI for understanding fetal neurodevelopment. Here, we bridge this gap by applying a novel application of deep 3D CNN to fetal blood oxygen-level dependence (BOLD) resting-state fMRI data. Specifically, we test a supervised CNN framework as a data-driven approach to isolate variation in fMRI signals that relate to younger v.s. older fetal age groups. Based on the learned CNN, we further perform sensitivity analysis to identify brain regions in which changes in BOLD signal are strongly associated with fetal brain age. The findings demonstrate that deep CNNs are a promising approach for identifying spontaneous functional patterns in fetal brain activity that discriminate age groups. Further, we discovered that regions that most strongly differentiate groups are largely bilateral, share similar distribution in older and younger age groups, and are areas of heightened metabolic activity in early human development.Comment: 9 page

Multivariate consistency of resting-state fMRI connectivity maps acquired on a single individual over 2.5 years, 13 sites and 3 vendors

Studies using resting-state functional magnetic resonance imaging (rsfMRI) are increasingly collecting data at multiple sites in order to speed up recruitment or increase sample size. The main objective of this study was to assess the long-term consistency of rsfMRI connectivity maps derived at multiple sites and vendors using the Canadian Dementia Imaging Protocol (CDIP, www.cdip-pcid.ca). Nine to 10 min of functional BOLD images were acquired from an adult cognitively healthy volunteer scanned repeatedly at 13 Canadian sites on three scanner makes (General Electric, Philips and Siemens) over the course of 2.5 years. The consistency (spatial Pearson’s correlation) of rsfMRI connectivity maps for seven canonical networks ranged from 0.3 to 0.8, with a negligible effect of time, but significant site and vendor effects. We noted systematic differences in data quality (i.e. head motion, number of useable time frames, temporal signal-to-noise ratio) across vendors, which may also confound some of these results, and could not be disentangled in this sample. We also pooled the long-term longitudinal data with a single-site, short-term (1 month) data sample acquired on 26 subjects (10 scans per subject), called HNU1. Using randomly selected pairs of scans from each subject, we quantified the ability of a data-driven unsupervised cluster analysis to match two scans of the same subjects. In this “fingerprinting” experiment, we found that scans from the Canadian subject (Csub) could be matched with high accuracy intra-site (>95% for some networks), but that the accuracy decreased substantially for scans drawn from different sites and vendors, even falling outside of the range of accuracies observed in HNU1. Overall, our results demonstrate good multivariate stability of rsfMRI measures over several years, but substantial impact of scanning site and vendors. How detrimental these effects are will depend on the application, yet our results demonstrate that new methods for harmonizing multisite analysis represent an important area for future work

BolT: Fused Window Transformers for fMRI Time Series Analysis

Deep-learning models have enabled performance leaps in analysis of high-dimensional functional MRI (fMRI) data. Yet, many previous methods are suboptimally sensitive for contextual representations across diverse time scales. Here, we present BolT, a blood-oxygen-level-dependent transformer model, for analyzing multi-variate fMRI time series. BolT leverages a cascade of transformer encoders equipped with a novel fused window attention mechanism. Encoding is performed on temporally-overlapped windows within the time series to capture local representations. To integrate information temporally, cross-window attention is computed between base tokens in each window and fringe tokens from neighboring windows. To gradually transition from local to global representations, the extent of window overlap and thereby number of fringe tokens are progressively increased across the cascade. Finally, a novel cross-window regularization is employed to align high-level classification features across the time series. Comprehensive experiments on large-scale public datasets demonstrate the superior performance of BolT against state-of-the-art methods. Furthermore, explanatory analyses to identify landmark time points and regions that contribute most significantly to model decisions corroborate prominent neuroscientific findings in the literature

Predicting Brain Age Based on Spatial and Temporal Features of Human Brain Functional Networks

The organization of human brain networks can be measured by capturing correlated brain activity with functional MRI data. There have been a variety of studies showing that human functional connectivities undergo an age-related change over development. In the present study, we employed resting-state functional MRI data to construct functional network models. Principal component analysis was performed on the FC matrices across all the subjects to explore meaningful components especially correlated with age. Coefficients across the components, edge features after a newly proposed feature reduction method as well as temporal features based on fALFF, were extracted as predictor variables and three different regression models were learned to make prediction of brain age. We observed that individual's functional network architecture was shaped by intrinsic component, age-related component and other components and the predictive models extracted sufficient information to provide comparatively accurate predictions of brain age

Large-scale neuroimaging in Alzheimer’s disease and normal aging

Large-scale neuroimaging data is becoming increasingly available, providing a rich data source with which to study neurological conditions. In this thesis, I demonstrate the utility of large-scale neuroimaging as it applies to Alzheimer’s disease (AD) and normal aging, using univariate parametric mapping, regional analysis, and advanced machine learning. Specifically, this thesis covers: 1) validation and extension of prior studies using large-scale datasets; 2) AD diagnosis and normal aging evaluation empowered by large-scale datasets and advanced deep learning algorithms; 3) enhancement of cerebral blood volume (CBV) fMRI utility with retrospective CBV-fMRI technique. First, I demonstrated the utility of large-scale datasets for validating and extending prior studies using univariate analytics. I presented a study localizing AD-vulnerable regions more reliably and with better anatomical resolution using data from more than 350 subjects. Following a similar approach, I investigated the structural characteristics of healthy APOE ε4 homozygous subjects screened from a large-scale community-based study. To study the neuroimaging signatures of normal aging, we performed a large-scale joint CBV-fMRI and structural MRI study covering age 20-70s, and a structural MRI study of normal aging covering the full age-span, with the elder group screened from a large-scale clinic-based study ensuring no evidence of AD using both longitudinal follow-up and cerebrospinal fluid (CSF) biomarkers evidences. Second, I performed deep learning neuroimaging studies for AD diagnosis and normal aging evaluation, and investigated the regionality associated with each task. I developed an AD diagnosis method using a 3D convolutional neural network model trained and evaluated on ~4,600 structural MRI scans and further investigated a series of novel regionality analyses. I further extensively studied the utility of the structural MRI summary measure derived from the deep learning model in prodromal AD detection. This study constitutes a general analytic framework, which was followed to evaluate normal aging by performing deep learning-based age estimation in cognitively normal population using more than 6,000 scans. The deep learning neuroimaging models classified AD and estimated age with high accuracy, and also revealed regional patterns conforming to neuropathophysiology. The deep learning derived MRI measure demonstrated potential clinical utility, outperforming other AD pathology measures and biomarkers. In addition, I explored the utility of deep learning on positron emission tomography (PET) data for AD diagnosis and regionality analyses, further demonstrating the broad utility and generalizability of the method. Finally, I introduced a technique enabling CBV generation retrospectively from clinical contrast-enhanced scans. The derivation of meaningful functional measures from such clinical scans is only possible through calibration to a reference, which was built from the largest collection of research CBV-fMRI scans from our lab. This method was validated in an epilepsy study and demonstrated the potential to enhance the utility of CBV-fMRI by enriching the CBV-fMRI dataset. This technique is also applicable to AD and normal aging studies, and potentially enables deep learning based analytic approaches applied on CBV-fMRI with similar pipelines used in structural MRI. Collectively, this thesis demonstrates how mechanistic and diagnostic information on brain disorders can be extracted from large-scale neuroimaging data, using both classical statistical methods and advanced machine learning