Leveraging multi-site electronic health data for characterization of subtypes: a pilot study of dementia in the N3C Clinical Tenant.

Objectives: To provide a foundational methodology for differentiating comorbidity patterns in subphenotypes through investigation of a multi-site dementia patient dataset. Materials and Methods: Employing the National Clinical Cohort Collaborative Tenant Pilot (N3C Clinical) dataset, our approach integrates machine learning algorithms-logistic regression and eXtreme Gradient Boosting (XGBoost)-with a diagnostic hierarchical model for nuanced classification of dementia subtypes based on comorbidities and gender. The methodology is enhanced by multi-site EHR data, implementing a hybrid sampling strategy combining 65% Synthetic Minority Over-sampling Technique (SMOTE), 35% Random Under-Sampling (RUS), and Tomek Links for class imbalance. The hierarchical model further refines the analysis, allowing for layered understanding of disease patterns. Results: The study identified significant comorbidity patterns associated with diagnosis of Alzheimer's, Vascular, and Lewy Body dementia subtypes. The classification models achieved accuracies up to 69% for Alzheimer's/Vascular dementia and highlighted challenges in distinguishing Dementia with Lewy Bodies. The hierarchical model elucidates the complexity of diagnosing Dementia with Lewy Bodies and reveals the potential impact of regional clinical practices on dementia classification. Conclusion: Our methodology underscores the importance of leveraging multi-site datasets and tailored sampling techniques for dementia research. This framework holds promise for extending to other disease subtypes, offering a pathway to more nuanced and generalizable insights into dementia and its complex interplay with comorbid conditions. Discussion: This study underscores the critical role of multi-site data analyzes in understanding the relationship between comorbidities and disease subtypes. By utilizing diverse healthcare data, we emphasize the need to consider site-specific differences in clinical practices and patient demographics. Despite challenges like class imbalance and variability in EHR data, our findings highlight the essential contribution of multi-site data to developing accurate and generalizable models for disease classification.

Assessment of Sports Concussion in Female Athletes: A Role for Neuroinformatics?

Over the past decade, the intricacies of sports-related concussions among female athletes have become readily apparent. Traditional clinical methods for diagnosing concussions suffer limitations when applied to female athletes, often failing to capture subtle changes in brain structure and function. Advanced neuroinformatics techniques and machine learning models have become invaluable assets in this endeavor. While these technologies have been extensively employed in understanding concussion in male athletes, there remains a significant gap in our comprehension of their effectiveness for female athletes. With its remarkable data analysis capacity, machine learning offers a promising avenue to bridge this deficit. By harnessing the power of machine learning, researchers can link observed phenotypic neuroimaging data to sex-specific biological mechanisms, unraveling the mysteries of concussions in female athletes. Furthermore, embedding methods within machine learning enable examining brain architecture and its alterations beyond the conventional anatomical reference frame. In turn, allows researchers to gain deeper insights into the dynamics of concussions, treatment responses, and recovery processes. This paper endeavors to address the crucial issue of sex differences in multimodal neuroimaging experimental design and machine learning approaches within female athlete populations, ultimately ensuring that they receive the tailored care they require when facing the challenges of concussions. Through better data integration, feature identification, knowledge representation, validation, etc., neuroinformaticists, are ideally suited to bring clarity, context, and explainabilty to the study of sports-related head injuries in males and in females, and helping to define recovery.

High baseline perivascular space volume in basal ganglia is associated with attention and executive function decline in Parkinson's disease.

BACKGROUND: Pathologic perivascular spaces (PVS), the fluid-filled compartments surrounding brain vasculature, may underlie cognitive decline in Parkinson's disease (PD). However, whether this impacts specific cognitive domains has not been investigated. OBJECTIVES: This study examined the relationship of PVS volume at baseline with domain-specific and global cognitive change over 2 years in PD individuals. METHODS: A total of 39 individuals with PD underwent 3T T1w magnetic resonance imaging to determine PVS volume fraction (PVS volume normalized to total regional volume) within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, and superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of cognitive domains and global cognitive function at baseline and after 2 years. RESULTS: Higher basal ganglia PVS at baseline was associated with greater decline in attention, executive function, and global cognition scores. CONCLUSIONS: While previous reports have associated elevated PVS volume in the basal ganglia with decline in global cognition in PD, our findings show such decline may affect the attention and executive function domains.

Data-driven sequence of cognitive decline in people with Parkinson's disease.

BACKGROUND: Understanding the sequential progression of cognitive impairments in Parkinson's disease (PD) is crucial for elucidating neuropathological underpinnings, refining the assessment of PD-related cognitive decline stages and enhancing early identification for targeted interventions. The first aim of this study was to use an innovative event-based modeling (EBM) analytic approach to estimate the sequence of cognitive declines in PD. The second aim was to validate the EBM by examining associations with EBM-derived individual-specific estimates of cognitive decline severity and performance on independent cognitive screening measures. METHODS: This cross-sectional observational study included 99 people with PD who completed a neuropsychological battery. Individuals were classified as meeting the criteria for mild cognitive impairment (PD-MCI) or subtle cognitive decline by consensus. An EBM was constructed to compare cognitively healthy individuals with those with PD-MCI or subtle cognitive disturbances. Multivariable linear regression estimated associations between the EBM-derived stage of cognitive decline and performance on two independent cognitive screening tests. RESULTS: The EBM estimated that tests assessing executive function and visuospatial ability become abnormal early in the sequence of PD-related cognitive decline. Each higher estimated stage of cognitive decline was associated with approximately 0.24 worse performance on the Dementia Rating Scale (p<0.001) and 0.26 worse performance on the Montreal Cognitive Assessment (p<0.001) adjusting for demographic and clinical variables. CONCLUSION: Findings from this study will have important clinical implications for practitioners, on specific cognitive tests to prioritise, when conducting neuropsychological evaluations with people with PD. Results also highlight the importance of frontal-subcortical system disruption impacting executive and visuospatial abilities.

Conduction velocity, G-ratio, and extracellular water as microstructural characteristics of autism spectrum disorder.

The neuronal differences contributing to the etiology of autism spectrum disorder (ASD) are still not well defined. Previous studies have suggested that myelin and axons are disrupted during development in ASD. By combining structural and diffusion MRI techniques, myelin and axons can be assessed using extracellular water, aggregate g-ratio, and a new approach to calculating axonal conduction velocity termed aggregate conduction velocity, which is related to the capacity of the axon to carry information. In this study, several innovative cellular microstructural methods, as measured from magnetic resonance imaging (MRI), are combined to characterize differences between ASD and typically developing adolescent participants in a large cohort. We first examine the relationship between each metric, including microstructural measurements of axonal and intracellular diffusion and the T1w/T2w ratio. We then demonstrate the sensitivity of these metrics by characterizing differences between ASD and neurotypical participants, finding widespread increases in extracellular water in the cortex and decreases in aggregate g-ratio and aggregate conduction velocity throughout the cortex, subcortex, and white matter skeleton. We finally provide evidence that these microstructural differences are associated with higher scores on the Social Communication Questionnaire (SCQ) a commonly used diagnostic tool to assess ASD. This study is the first to reveal that ASD involves MRI-measurable in vivo differences of myelin and axonal development with implications for neuronal and behavioral function. We also introduce a novel formulation for calculating aggregate conduction velocity, that is highly sensitive to these changes. We conclude that ASD may be characterized by otherwise intact structural connectivity but that functional connectivity may be attenuated by network properties affecting neural transmission speed. This effect may explain the putative reliance on local connectivity in contrast to more distal connectivity observed in ASD.

Biophysical modulation and robustness of itinerant complexity in neuronal networks.

Transient synchronization of bursting activity in neuronal networks, which occurs in patterns of metastable itinerant phase relationships between neurons, is a notable feature of network dynamics observed in vivo. However, the mechanisms that contribute to this dynamical complexity in neuronal circuits are not well understood. Local circuits in cortical regions consist of populations of neurons with diverse intrinsic oscillatory features. In this study, we numerically show that the phenomenon of transient synchronization, also referred to as metastability, can emerge in an inhibitory neuronal population when the neurons' intrinsic fast-spiking dynamics are appropriately modulated by slower inputs from an excitatory neuronal population. Using a compact model of a mesoscopic-scale network consisting of excitatory pyramidal and inhibitory fast-spiking neurons, our work demonstrates a relationship between the frequency of pyramidal population oscillations and the features of emergent metastability in the inhibitory population. In addition, we introduce a method to characterize collective transitions in metastable networks. Finally, we discuss potential applications of this study in mechanistically understanding cortical network dynamics.

Increased perivascular space volume in white matter and basal ganglia is associated with cognition in Parkinson's Disease.

Perivascular spaces (PVS), fluid-filled compartments surrounding brain vasculature, are an essential component of the glymphatic system responsible for transport of waste and nutrients. Glymphatic system impairment may underlie cognitive deficits in Parkinson's disease (PD). Studies have focused on the role of basal ganglia PVS with cognition in PD, but the role of white matter PVS is unknown. This study examined the relationship of white matter and basal ganglia PVS with domain-specific and global cognition in individuals with PD. Fifty individuals with PD underwent 3T T1w magnetic resonance imaging (MRI) to determine PVS volume fraction, defined as PVS volume normalized to total regional volume, within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of global cognitive function (Montreal Cognitive Assessment, and global cognitive composite score), and cognitive-specific domains (executive function, memory, visuospatial function, attention, and language). Higher white matter rostral middle frontal PVS was associated with lower scores in both global cognitive and visuospatial function. In the basal ganglia higher PVS was associated with lower scores for memory with a trend towards lower global cognitive composite score. While previous reports have shown that greater amount of PVS in the basal ganglia is associated with decline in global cognition in PD, our findings suggest that increased white matter PVS volume may also underlie changes in cognition.

Conduction Velocity, G-ratio, and Extracellular Water as Microstructural Characteristics of Autism Spectrum Disorder.

The neuronal differences contributing to the etiology of autism spectrum disorder (ASD) are still not well defined. Previous studies have suggested that myelin and axons are disrupted during development in ASD. By combining structural and diffusion MRI techniques, myelin and axons can be assessed using extracellular water, aggregate g-ratio, and a novel metric termed aggregate conduction velocity, which is related to the capacity of the axon to carry information. In this study, several innovative cellular microstructural methods, as measured from magnetic resonance imaging (MRI), are combined to characterize differences between ASD and typically developing adolescent participants in a large cohort. We first examine the relationship between each metric, including microstructural measurements of axonal and intracellular diffusion and the T1w/T2w ratio. We then demonstrate the sensitivity of these metrics by characterizing differences between ASD and neurotypical participants, finding widespread increases in extracellular water in the cortex and decreases in aggregate g-ratio and aggregate conduction velocity throughout the cortex, subcortex, and white matter skeleton. We finally provide evidence that these microstructural differences are associated with higher scores on the Social Communication Questionnaire (SCQ) a commonly used diagnostic tool to assess ASD. This study is the first to reveal that ASD involves MRI-measurable in vivo differences of myelin and axonal development with implications for neuronal and behavioral function. We also introduce a novel neuroimaging metric, aggregate conduction velocity, that is highly sensitive to these changes. We conclude that ASD may be characterized by otherwise intact structural connectivity but that functional connectivity may be attenuated by network properties affecting neural transmission speed. This effect may explain the putative reliance on local connectivity in contrast to more distal connectivity observed in ASD.

Physical activity intensity is associated with cognition and functional connectivity in Parkinson's disease.

BACKGROUND: Cognitive impairment is common in Parkinson's disease (PD) and often leads to dementia, with no effective treatment. Aging studies suggest that physical activity (PA) intensity has a positive impact on cognition and enhanced functional connectivity may underlie these benefits. However, less is known in PD. This cross-sectional study examined the relationship between PA intensity, cognitive performance, and resting state functional connectivity in PD and whether PA intensity influences the relationship between functional connectivity and cognitive performance. METHODS: 96 individuals with mild-moderate PD completed a comprehensive neuropsychological battery. Intensity of PA was objectively captured over a seven-day period using a wearable device (ActiGraph). Time spent in light and moderate intensity PA was determined based on standardized actigraphy cut points. Resting-state fMRI was assessed in a subset of 50 individuals to examine brain-wide functional connectivity. RESULTS: Moderate intensity PA (MIPA), but not light PA, was associated with better global cognition, visuospatial function, memory, and executive function. Individuals who met the WHO recommendation of ≥150 min/week of MIPA demonstrated better global cognition, executive function, and visuospatial function. Resting-state functional connectivity associated with MIPA included a combination of brainstem, hippocampus, and regions in the frontal, cingulate, and parietal cortices, which showed higher connectivity across the brain in those achieving the WHO MIPA recommendation. Meeting this recommendation positively moderated the associations between identified functional connectivity and global cognition, visuospatial function, and language. CONCLUSION: Encouraging MIPA, particularly the WHO recommendation of ≥150 min of MIPA/week, may represent an important prescription for PD cognition.

Session Introduction: Big Data Imaging Genomics.

This PSB 2022 session addresses challenges and solutions in translating Big Data Imaging Genomics research towards personalized medicine and guiding individual clinical decisions. We will focus on Big Data analyses, pattern recognition, machine learning and AI, electronic health records, guiding diagnostic and treatment decisions and reports of state-of-the-art findings from large and diverse imaging, genomics, and other biomedical datasets.

Integrative Models of Brain Structure and Dynamics: Concepts, Challenges, and Methods.

The anatomical architecture of the brain constrains the dynamics of interactions between various regions. On a microscopic scale, neural plasticity regulates the connections between individual neurons. This microstructural adaptation facilitates coordinated dynamics of populations of neurons (mesoscopic scale) and brain regions (macroscopic scale). However, the mechanisms acting on multiple timescales that govern the reciprocal relationship between neural network structure and its intrinsic dynamics are not well understood. Studies empirically investigating such relationships on the whole-brain level rely on macroscopic measurements of structural and functional connectivity estimated from various neuroimaging modalities such as Diffusion-weighted Magnetic Resonance Imaging (dMRI), Electroencephalography (EEG), Magnetoencephalography (MEG), and functional Magnetic Resonance Imaging (fMRI). dMRI measures the anisotropy of water diffusion along axonal fibers, from which structural connections are estimated. EEG and MEG signals measure electrical activity and magnetic fields induced by the electrical activity, respectively, from various brain regions with a high temporal resolution (but limited spatial coverage), whereas fMRI measures regional activations indirectly via blood oxygen level-dependent (BOLD) signals with a high spatial resolution (but limited temporal resolution). There are several studies in the neuroimaging literature reporting statistical associations between macroscopic structural and functional connectivity. On the other hand, models of large-scale oscillatory dynamics conditioned on network structure (such as the one estimated from dMRI connectivity) provide a platform to probe into the structure-dynamics relationship at the mesoscopic level. Such investigations promise to uncover the theoretical underpinnings of the interplay between network structure and dynamics and could be complementary to the macroscopic level inquiries. In this article, we review theoretical and empirical studies that attempt to elucidate the coupling between brain structure and dynamics. Special attention is given to various clinically relevant dimensions of brain connectivity such as the topological features and neural synchronization, and their applicability for a given modality, spatial or temporal scale of analysis is discussed. Our review provides a summary of the progress made along this line of research and identifies challenges and promising future directions for multi-modal neuroimaging analyses.

Mapping the rest of the human connectome: Atlasing the spinal cord and peripheral nervous system.

The emergence of diffusion, structural, and functional neuroimaging methods has enabled major multi-site efforts to map the human connectome, which has heretofore been defined as containing all neural connections in the central nervous system (CNS). However, these efforts are not structured to examine the richness and complexity of the peripheral nervous system (PNS), which arguably forms the (neglected) rest of the connectome. Despite increasing interest in an atlas of the spinal cord (SC) and PNS which is simultaneously stereotactic, interactive, electronically dissectible, scalable, population-based and deformable, little attention has thus far been devoted to this task of critical importance. Nevertheless, the atlasing of these complete neural structures is essential for neurosurgical planning, neurological localization, and for mapping those components of the human connectome located outside of the CNS. Here we recommend a modification to the definition of the human connectome to include the SC and PNS, and argue for the creation of an inclusive atlas to complement current efforts to map the brain's human connectome, to enhance clinical education, and to assist progress in neuroscience research. In addition to providing a critical overview of existing neuroimaging techniques, image processing methodologies and algorithmic advances which can be combined for the creation of a full connectome atlas, we outline a blueprint for ultimately mapping the entire human nervous system and, thereby, for filling a critical gap in our scientific knowledge of neural connectivity.

Bridging the Brain and Data Sciences.

Brain scientists are now capable of collecting more data in a single experiment than researchers a generation ago might have collected over an entire career. Indeed, the brain itself seems to thirst for more and more data. Such digital information not only comprises individual studies but is also increasingly shared and made openly available for secondary, confirmatory, and/or combined analyses. Numerous web resources now exist containing data across spatiotemporal scales. Data processing workflow technologies running via cloud-enabled computing infrastructures allow for large-scale processing. Such a move toward greater openness is fundamentally changing how brain science results are communicated and linked to available raw data and processed results. Ethical, professional, and motivational issues challenge the whole-scale commitment to data-driven neuroscience. Nevertheless, fueled by government investments into primary brain data collection coupled with increased sharing and community pressure challenging the dominant publishing model, large-scale brain and data science is here to stay.

Neuroimaging of traumatic brain injury in military personnel: An overview.

BACKGROUND: The incidence of blunt-force traumatic brain injury (TBI) is especially prevalent in the military, where the emergency care admission rate has been reported to be 24.6-41.8 per 10,000 soldier-years. Given substantial advancements in modern neuroimaging techniques over the past decade in terms of structural, functional, and connectomic approaches, this mode of exploration can be viewed as best suited for understanding the underlying pathology and for providing proper intervention at effective time-points. APPROACH: Here we survey neuroimaging studies of mild-to-severe TBI in military veterans with the intent to aid the field in the creation of a roadmap for clinicians and researchers whose aim is to understand TBI progression. DISCUSSION: Recent advancements on the quantification of neurocognitive dysfunction, cellular dysfunction, intracranial pressure, cerebral blood flow, inflammation, post-traumatic neuropathophysiology, on blood serum biomarkers and on their correlation to neuroimaging findings are reviewed to hypothesize how they can be used in conjunction with one another. This may allow clinicians and scientists to comprehensively study TBI in military service members, leading to new treatment strategies for both currently-serving as well as veteran personnel, and to improve the study of TBI more broadly.