Faculty Bibliography

BACKGROUND:Mild traumatic brain injury is theorized to cause widespread functional changes to the brain. Resting-state fMRI may be able to measure functional connectivity changes after traumatic brain injury, but resting-state fMRI studies are heterogeneous, using numerous techniques to study ROIs across various resting-state networks. PURPOSE/OBJECTIVE:We systematically reviewed the literature to ascertain whether adult patients who have experienced mild traumatic brain injury show consistent functional connectivity changes on resting-state -fMRI, compared with healthy patients. DATA SOURCES/METHODS:We used 5 databases (PubMed, EMBASE, Cochrane Central, Scopus, Web of Science). STUDY SELECTION/METHODS:Five databases (PubMed, EMBASE, Cochrane Central, Scopus, and Web of Science) were searched for research published since 2010. Search strategies used keywords of "functional MR imaging" and "mild traumatic brain injury" as well as related terms. All results were screened at the abstract and title levels by 4 reviewers according to predefined inclusion and exclusion criteria. For full-text inclusion, each study was evaluated independently by 2 reviewers, with discordant screening settled by consensus. DATA ANALYSIS/METHODS:Data regarding article characteristics, cohort demographics, fMRI scan parameters, data analysis processing software, atlas used, data characteristics, and statistical analysis information were extracted. DATA SYNTHESIS/RESULTS:Across 66 studies, 80 areas were analyzed 239 times for at least 1 time point, most commonly using independent component analysis. The most analyzed areas and networks were the whole brain, the default mode network, and the salience network. Reported functional connectivity changes varied, though there may be a slight trend toward decreased whole-brain functional connectivity within 1 month of traumatic brain injury and there may be differences based on the time since injury. LIMITATIONS/CONCLUSIONS:Studies of military, sports-related traumatic brain injury, and pediatric patients were excluded. Due to the high number of relevant studies and data heterogeneity, we could not be as granular in the analysis as we would have liked. CONCLUSIONS:Reported functional connectivity changes varied, even within the same region and network, at least partially reflecting differences in technical parameters, preprocessing software, and analysis methods as well as probable differences in individual injury. There is a need for novel rs-fMRI techniques that better capture subject-specific functional connectivity changes.

Biological sex is a crucial variable in neuroscience studies where sex differences have been documented across cognitive functions and neuropsychiatric disorders. While gross statistical differences have been previously documented in macroscopic brain structure such as cortical thickness or region size, less is understood about sex-related cellular-level microstructural differences which could provide insight into brain health and disease. Studying these microstructural differences between men and women paves the way for understanding brain disorders and diseases that manifest differently in different sexes. Diffusion MRI is an important in vivo, non-invasive methodology that provides a window into brain tissue microstructure. Our study develops multiple end-to-end classification models that accurately estimates the sex of a subject using volumetric diffusion MRI data and uses these models to identify white matter regions that differ the most between men and women. 471 male and 560 female healthy subjects (age range, 22-37 years) from the Human Connectome Project are included. Fractional anisotropy, mean diffusivity and mean kurtosis are used to capture brain tissue microstructure characteristics. Diffusion parametric maps are registered to a standard template to reduce bias that can arise from macroscopic anatomical differences like brain size and contour. This study employ three major model architectures: 2D convolutional neural networks, 3D convolutional neural networks and Vision Transformer (with self-supervised pretraining). Our results show that all 3 models achieve high sex classification performance (test AUC 0.92-0.98) across all diffusion metrics indicating definitive differences in white matter tissue microstructure between males and females. We further use complementary model architectures to inform about the pattern of detected microstructural differences and the influence of short-range versus long-range interactions. Occlusion analysis together with Wilcoxon signed-rank test is used to determine which white matter regions contribute most to sex classification. The results indicate that sex-related differences manifest in both local features as well as global features / longer-distance interactions of tissue microstructure. Our highly consistent findings across models provides new insight supporting differences between male and female brain cellular-level tissue organization particularly in the central white matter.

BACKGROUND AND PURPOSE/OBJECTIVE:Several recent works using resting-state fMRI suggest possible alterations of resting-state functional connectivity after mild traumatic brain injury. However, the literature is plagued by various analysis approaches and small study cohorts, resulting in an inconsistent array of reported findings. In this study, we aimed to investigate differences in whole-brain resting-state functional connectivity between adult patients with mild traumatic brain injury within 1 month of injury and healthy control subjects using several comprehensive resting-state functional connectivity measurement methods and analyses. MATERIALS AND METHODS/METHODS:A total of 123 subjects (72 patients with mild traumatic brain injury and 51 healthy controls) were included. A standard fMRI preprocessing pipeline was used. ROI/seed-based analyses were conducted using 4 standard brain parcellation methods, and the independent component analysis method was applied to measure resting-state functional connectivity. The fractional amplitude of low-frequency fluctuations was also measured. Group comparisons were performed on all measurements with appropriate whole-brain multilevel statistical analysis and correction. RESULTS:There were no significant differences in age, sex, education, and hand preference between groups as well as no significant correlation between all measurements and these potential confounders. We found that each resting-state functional connectivity measurement revealed various regions or connections that were different between groups. However, after we corrected for multiple comparisons, the results showed no statistically significant differences between groups in terms of resting-state functional connectivity across methods and analyses. CONCLUSIONS:Although previous studies point to multiple regions and networks as possible mild traumatic brain injury biomarkers, this study shows that the effect of mild injury on brain resting-state functional connectivity has not survived after rigorous statistical correction. A further study using subject-level connectivity analyses may be necessary due to both subtle and variable effects of mild traumatic brain injury on brain functional connectivity across individuals.

BACKGROUND AND PURPOSE/OBJECTIVE:Because the corpus callosum connects the left and right hemispheres and a variety of WM bundles across the brain in complex ways, damage to the neighboring WM microstructure may specifically disrupt interhemispheric communication through the corpus callosum following mild traumatic brain injury. Here we use a mediation framework to investigate how callosal interhemispheric communication is affected by WM microstructure in mild traumatic brain injury. MATERIALS AND METHODS/METHODS:Multishell diffusion MR imaging was performed on 23 patients with mild traumatic brain injury within 1 month of injury and 17 healthy controls, deriving 11 diffusion metrics, including DTI, diffusional kurtosis imaging, and compartment-specific standard model parameters. Interhemispheric processing speed was assessed using the interhemispheric speed of processing task (IHSPT) by measuring the latency between word presentation to the 2 hemivisual fields and oral word articulation. Mediation analysis was performed to assess the indirect effect of neighboring WM microstructures on the relationship between the corpus callosum and IHSPT performance. In addition, we conducted a univariate correlation analysis to investigate the direct association between callosal microstructures and IHSPT performance as well as a multivariate regression analysis to jointly evaluate both callosal and neighboring WM microstructures in association with IHSPT scores for each group. RESULTS:Several significant mediators in the relationships between callosal microstructure and IHSPT performance were found in healthy controls. However, patients with mild traumatic brain injury appeared to lose such normal associations when microstructural changes occurred compared with healthy controls. CONCLUSIONS:This study investigates the effects of neighboring WM microstructure on callosal interhemispheric communication in healthy controls and patients with mild traumatic brain injury, highlighting that neighboring noncallosal WM microstructures are involved in callosal interhemispheric communication and information transfer. Further longitudinal studies may provide insight into the temporal dynamics of interhemispheric recovery following mild traumatic brain injury.

The corpus callosum (CC) is the most important interhemispheric white matter (WM) structure composed of several anatomically and functionally distinct WM tracts. Resolving these tracts is a challenge since the callosum appears relatively homogenous in conventional structural imaging. Commonly used callosal parcellation methods such as the Hofer/Frahm scheme rely on rigid geometric guidelines to separate the substructures that are limited to consider individual variation. Here we present a novel subject-specific and microstructurally-informed method for callosal parcellation based on axonal water fraction (ƒ) known as a diffusion metric reflective of axon caliber and density. We studied 30 healthy subjects from the Human Connectome Project (HCP) dataset with multi-shell diffusion MRI. The biophysical parameter ƒ was derived from compartment-specific WM modeling. Inflection points were identified where there were concavity changes in ƒ across the CC to delineate callosal subregions. We observed relatively higher ƒ in anterior and posterior areas consisting of a greater number of small diameter fibers and lower ƒ in posterior body areas of the CC consisting of a greater number of large diameter fibers. Based on degree of change in ƒ along the callosum, seven callosal subregions can be consistently delineated for each individual. We observe that ƒ can capture differences in underlying tissue microstructures and seven subregions can be identified across CC. Therefore, this method provides microstructurally informed callosal parcellation in a subject-specific way, allowing for more accurate analysis in the corpus callosum.

PURPOSE/OBJECTIVE:Repeated head impacts (RHI) without concussion may cause long-term sequelae. A growing array of diffusion MRI metrics exist, both empiric and modeled and it is hard to know which are potentially important biomarkers. Common conventional statistical methods fail to consider interactions between metrics and rely on group-level comparisons. This study uses a classification pipeline as a means towards identifying important diffusion metrics associated with subconcussive RHI. METHODS:36 collegiate contact sport athletes and 45 non-contact sport controls from FITBIR CARE were included. Regional/whole brain WM statistics were computed from 7 diffusion metrics. Wrapper-based feature selection was applied to 5 classifiers representing a range of learning capacities. Best 2 classifiers were interpreted to identify the most RHI-related diffusion metrics. RESULTS:Mean diffusivity (MD) and mean kurtosis (MK) are found to be the most important metrics for discriminating between athletes with and without RHI exposure history. Regional features outperformed global statistics. Linear approaches outperformed non-linear approaches with good generalizability (test AUC 0.80-0.81). CONCLUSION/CONCLUSIONS:) are found to be the most influential metrics. This work provides proof of concept that applying such approach to small, multidimensional dataset can be successful given attention to optimizing learning capacity without overfitting and serves an example of methods that lead to better understanding of the myriad of diffusion metrics as they relate to injury and disease.

The thalamus consists of several functionally distinct nuclei, some of which serve as targets for functional neurosurgery. Visualization of such nuclei is a major challenge due to their low signal contrast on conventional imaging. We introduce MR susceptibility imaging with a short TE, leveraging susceptibility differences among thalamic nuclei, to automatically delineate 15 thalamic subregions. The technique has the potential to enable direct targeting of thalamic nuclei for functional neurosurgical guidance.

Quantitative, volumetric analysis of Magnetic Resonance Imaging (MRI) is a fundamental way researchers study the brain in a host of neurological conditions including normal maturation and aging. Despite the availability of open-source brain segmentation software, widespread clinical adoption of volumetric analysis has been hindered due to processing times and reliance on manual corrections. Here, we extend the use of deep learning models from proof-of-concept, as previously reported, to present a comprehensive segmentation of cortical and deep gray matter brain structures matching the standard regions of aseg+ aparc included in the commonly used open-source tool, Freesurfer. The work presented here provides a real-life, rapid deep learning-based brain segmentation tool to enable clinical translation as well as research application of quantitative brain segmentation. The advantages of the presented tool include short (~ 1 minute) processing time and improved segmentation quality. This is the first study to perform quick and accurate segmentation of 102 brain regions based on the surface-based protocol (DMK protocol), widely used by experts in the field. This is also the first work to include an expert reader study to assess the quality of the segmentation obtained using a deep-learning-based model. We show the superior performance of our deep-learning-based models over the traditional segmentation tool, Freesurfer. We refer to the proposed deep learning-based tool as DARTS (DenseUnet-based Automatic Rapid Tool for brain Segmentation)

In this work, we propose bag of adversarial features (BAF) for identifying mild traumatic brain injury (MTBI) patients from their diffusion magnetic resonance images (MRI) (obtained within one month of injury) by incorporating unsupervised feature learning techniques. MTBI is a growing public health problem with an estimated incidence of over 1.7 million people annually in US. Diagnosis is based on clinical history and symptoms, and accurate, concrete measures of injury are lacking. Unlike most of previous works, which use hand-crafted features extracted from different parts of brain for MTBI classification, we employ feature learning algorithms to learn more discriminative representation for this task. A major challenge in this field thus far is the relatively small number of subjects available for training. This makes it difficult to use an end-to-end convolutional neural network to directly classify a subject from MR images. To overcome this challenge, we first apply an adversarial auto-encoder (with convolutional structure) to learn patch-level features, from overlapping image patches extracted from different brain regions. We then aggregate these features through a bag-of-word approach. We perform an extensive experimental study on a dataset of 227 subjects (including 109 MTBI patients, and 118 age and sex matched healthy controls), and compare the bag-of-deep-features with several previous approaches. Our experimental results show that the BAF significantly outperforms earlier works relying on the mean values of MR metrics in selected brain regions.