Monica Fabiani - US grants

DESCRIPTION (provided by applicant): Common non-invasive methods for studying the human brain function, such as Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI), are based on imaging some of the consequences of neuronal activity (i.e., increased blood flow to active areas of the brain) rather than reflecting this activity directly. However, the relationship between neuronal activity and blood flow - neurovascular coupling - is not well understood. The assumption that this relationship is linear and similar across subjects, brain areas, and experimental conditions may not always be valid, especially when individuals of varying age and cardiopulmonary fitness levels are compared. One significant limitation of most studies testing the linearity assumption is that only the hemodynamic signal is manipulated and measured, without an independent measure of neuronal activity. In this proposal we intend to use a novel approach to the investigation of neurovascular coupling, based on recording non-invasive optical brain imaging data in young adults, and in older adults selected for being high or low in cardiopulmonary fitness. Optical methods provide simultaneously recorded but independent measures of hemodynamic (near-infra-red spectroscopy, or NIRS) and neuronal (the event-related optical signal, or EROS) activity. Event-related brain potentials (ERPs) and the BOLD fMRI response will also be recorded in the same subjects and conditions to provide an external validation to this approach. Our specific goals are to determine whether and under which conditions the overall relationship between neuronal and hemodynamic signals is linear; what are the parameters of this function, and whether they vary with age, fitness, area of the brain, and sensory, motor and cognitive load. This approach is intended to provide an empirical, systematic, and parametric methodology for describing the neurovascular coupling in different brain regions and subject populations. We believe that this approach will provide data that will help explicate the relationship between neuronal and vascular events and provide a bridge between neuronal and hemodynamic imaging methods.

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (01) Behavior, Behavioral Change, and Prevention and specific Challenge Topic, 01-AG-102: Neural mechanisms of behavioral change. Cognitive decline in normal aging is a very important societal problem, which impacts millions of people worldwide. Specifically, normal aging is accompanied by declines in working memory and executive function/attention control, as well as in long term memory and speed of processing. Thus, increasing knowledge about the possible predictors of age- related cognitive impairments and their interactions can yield substantial societal and economic benefits, by providing means of early detection and thus improving the chances of successful prevention and/or treatment. Recent studies have emphasized that physical activity and fitness may help stave off some of the effect of aging on cognition, and specifically those related to working memory and executive function, although the exact mechanisms through which these gains are obtained are not yet completely understood. In this work we will conduct a detailed investigation of the possible mediating role that the health status of the cerebrovascular system may have on the beneficial effects of physical fitness on brain anatomy and function and cognitive performance. Our approach is based on the assumption that all the phenomena under study (physical fitness/activity, cerebrovascular health, brain anatomy and function, and cognitive function) are in fact complex and multifaceted and best studied using a multivariate approach. Therefore, for each of them, we take multiple measures at multiple levels. We will investigate naturally-occurring variability in a sample of normally-aging adults comprising four age groups (50-60, 60-70, 70-80, and 80-90 years old), which will be measured twice at 12 months distance (thus affording both cross-sectional and short-term longitudinal analyses). A multimodal imaging approach based on a combination of magnetic resonance imaging, diffusive near-infrared spectroscopic imaging, and electrophysiological methods will be used to provide maps of both cerebrovascular status and brain anatomy and function. Societal Impact. Cognitive decline in aging affects millions of people worldwide. Its early detection may lead to prevention and improvement in intervention practices, thus providing incalculable benefits to society both in economic and humanitarian terms. Physical activity regimes have shown to be beneficial to cognitive aging. Therefore, a better understanding of the mechanisms through which these benefits are accrued is of enormous practical significance. In addition, following the guidelines of ARRA 2009 for these Challenge proposals, we underscore the fact that this proposal, if funded, will generate one new position (graduate research assistant) and allow for the retention of two additional positions (senior research scientist and research specialist) who may otherwise lose employment. It is further expected that, through this funding, these investigators will receive valuable training in the biomedical sciences, which will make them more competitive on job market in the future. PUBLIC HEALTH RELEVANCE: Cognitive decline in aging affects millions of people worldwide. Its early detection may lead to prevention and improvement in intervention practices, thus providing incalculable benefits to society both in economic and humanitarian terms. Physical activity regimes have shown to be beneficial to cognitive aging. Therefore, a better understanding of the mechanisms through which these benefits are accrued is of enormous practical significance. In addition, following the guidelines of ARRA 2009 for these Challenge proposals, we underscore the fact that this proposal, if funded, will generate one new position (graduate research assistant) and allow for the retention of two additional positions (senior research scientist and research specialist) who may otherwise lose employment. It is further expected that, through this funding, these investigators will receive valuable training in the biomedical sciences, which will make them more competitive on job market in the future.

This Integrative Education and Research Traineeship (IGERT) project will educate a diverse cadre of neuroscientists and engineers at the University of Illinois with an advanced understanding of both neuroscience and engineering, enabling them to engage in both sophisticated collaboration and independent research across the traditional gap between these domains. Many of the most important and exciting scientific and technological challenges for the future are centered on neuroscience, the study of the brain. Many recent (and most future) advances in understanding the brain depend on engineering new technologies for sensing, imaging, and analyzing the brain and their innovative use by neuroscientists. Similarly, some of the greatest and most important technological challenges, such as creating neural prostheses for the disabled, require engineers with a profound understanding of neuroscience. IGERT students will thus carry out innovative interdisciplinary research on neuroscience areas of great scientific and engineering importance, such as speech and audition, brain and imaging, and neural implants that may lead to revolutionary advances in understanding the brain and in new technologies such as neural prostheses for the disabled. IGERT trainees will also receive training in leadership, communication skills, and the responsible conduct of research as well as preparation for academic or industrial careers. IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to catalyze a cultural change in graduate education by establishing innovative new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries.

DESCRIPTION (provided by applicant): This project explores advancements in a method for imaging the function of the human brain, based on the measurements of changes in how near-infrared light diffuses through the brain (Diffuse Optical Tomography, DOT). This method is particularly useful to investigate the time course of rapid brain phenomena, such as neural activity, and the functional hemodynamic responses that follow neuronal activity in response to stimuli delivered during cognitive tasks. DOT can be applied to populations (such as small children or people who are claustrophobic or bearing metallic devices), who cannot be easily studied using other brain imaging technologies. It can also be concurrently used with standard methods such as functional magnetic resonance imaging (fMRI) and event-related brain potentials (ERPs) providing an important bridge for the understanding of the physiology underlying these methods. Importantly, DOT signals can potentially be useful in a large number of research and clinical applications, including the study of normal and abnormal brain activity in psychopathology, cognitive aging and dementia, development, and as a result of vascular brain problems, as well as for the study and diagnosis of cerebrovascular diseases from newborns to the elderly. A current limitation of this technique is that, in its current form, it only measures changes from a baseline level. In order to relate the functional data to particular brain structure, users have to rely on head-surface features or independently-collected structural MR-recordings. Here we explore the application of a methodology, called multi- distance approach, to generate absolute measurements of diffusion parameters over the entire cortical surface. These measurements can be used to reveal anatomical structures rich in hemoglobin (such as the venous sinuses), which can serve as useful anatomical landmarks for coregistration. Importantly, this structural information can be collected while recording the functional DOT data. The proposal will explore how reliable this information is, and how it can be used to precisely co-register the functional measures to anatomical brain structures. The proposed research will also explore how the transparency of the brain to near-infrared light changes with age. Preliminary data suggest strong age-related variations, with older adults showing significantly more brain transparency than younger adults. This difference may reflect changes in brain vascularization and/or cortical atrophy. The proposed research will explore the relevance of these factors, which may render this approach a useful tool for studying the health status of the cortex in a non-invasive manner. The absolute measurements of the light diffusion parameters also allows for a more quantitative study of functional DOT effects due to the activation of specific brain areas during cognitive tasks, and how they vary in different populations, as a function of age (and in principle, development and pathology). The proposed research will compare different methods for obtaining these functional images in term of their reliability, validity and signal-to-noise ratio.

Cerebrovascular health (and in particular arterial stiffening, or arteriosclerosis) is a significant contributor to age-related decline, and exerts a central role in a number of pathologies, including Alzheimer's disease (AD) and vascular dementia. Arteriosclerosis is progressive and considered to be irreversible. Therefore its early detection is of critical importance. As extensively demonstrated by the Framingham Heart Study and other longitudinal research, life style factors, and in particular physical inactivity, play a central role in the development of arteriosclerosis. Cerebral arteriosclerosis is currently assessed either indirectly with peripheral measures or more directly in the neck and head (with carotid or trans- cranial Doppler sonography, TCD), which provide useful clinical information but at just a few measurement points. Our lab has recently developed a new imaging approach, based on the study of the arterial pulse measured with diffuse optical tomography (pulse-DOT), which allows for the mapping of arterial status across the entire cortical mantle, with high reliability and replicability. We have shown that in normally aging older adults, low values of PReFx (pulse relaxation function, a measure of pulse shape indicative of arterial elasticity) are correlated with older age, lower cardiorespiratory fitness (CRF), and overall greater age-related brain atrophy and white matter signal abnormalities (WMSA). Crucially, we have also shown that local/regional variations in arterial stiffness from one brain region to another correlate with volumetric variations in the same regions. These regional effects provide a stronger functional link between arterial health and early structural signs of brain aging than those derived from global measures of arterial elasticity, pointing at the importance of arterial function in the chain of events that may lead, over time, to cognitive and brain volumetric losses. In the proposed research, based on a mixed cross-sectional/longitudinal (30 month) design involving 200 individuals between 50 and 70 years of age, we aim to: (1) Demonstrate that pulse-DOT will relate to cerebrovascular risk cross- sectionally and also prospectively over a 30-month period. Individuals classified by degree of presence of sub-clinical risk factors relating to low CRF are expected to show a graded relationship with the PReFx index of arterial stiffness, as well as with indices of cerebrovascular reactivity (CVR). Decreasing PReFx pulse-DOT values over follow-up are then expected to predict a worsening of risk. (2) Demonstrate that regional changes (over 30 months) in cerebral arterial function are associated with regional changes in brain structural (i.e., indicating signs of brain atrophy and WMSA) and blood flow parameters in the same regions (measured with magnetic resonance imaging, MRI). (3) Identify the relationship between cognitive function, regional vascular stiffening and CVR at baseline and over the follow-up period. We anticipate a concordance of regional deficits in vascular stiffening and vascular reactivity that will relate to specific deficits in cognitive processing. These findings should provide information not only on global effects of variations in cerebral arterial stiffness on brain and cognitive aging trajectories, but also on the regional profiles of arterial stiffness. In the long term this approach may provide a tool for studying cerebrovascular effects in basic and clinical applications, and for guiding individually tailored early interventions, designed to prevent age-related cognitive decline, MCI and AD.

PROJECT SUMMARY This proposal aims at using novel measures of regional cerebral arterial elasticity to clarify the role that arterial wall stiffening (arteriosclerosis) may play in age-related cognitive decline. In some older adults, cognitive decline becomes sufficiently severe to start impacting daily activities (mild cognitive impairment) and often progresses to Alzheimer's disease or other forms of dementia. Whereas dementia is considered to be irreversible, many of the risk factors contributing to it, including arteriosclerosis, are preventable, making the early detection of these conditions and of their specific roles in the pathway to cognitive decline, of paramount importance. In this proposal we focus on cognitive control functions, which are ubiquitous and crucial to everyday life, and include the setting, maintenance, and flexible adjustment of task goals representations. The overarching objective of this project is to systematically map the relationships between cerebrovascular, anatomical, functional, and behavioral variations in cognitive control over the adult life span (N=300, age range = 25-75, 60 people, 50% females per decade). We aim to determine whether profiles of regional variability in cerebrovascular function map onto individual differences in the structural and functional integrity of brain areas/networks that support cognitive control, and in the performance of cognitive control tasks. This approach is enabled by an innovative non-invasive optical imaging method, pulse-DOT (cerebral arterial pulse measured with diffuse optical tomography), which assesses the elasticity of cerebral arteries directly (instead of by inference from global, systemic measures) allowing us to map regional cerebral arterial stiffening with high signal to noise and reliability. In addition to pulse-DOT, individuals' profiles will include measures of (a) grey and white matter integrity; (b) brain function (MRI-based resting state functional connectivity [rsFC], event-related brain potentials [ERPs], and analysis of EEG oscillatory patterns); and (c) performance in behavioral paradigms investigating cognitive control. The specific aims of this proposal are to establish the relationships between individual differences in arterial elasticity in regions associated with cognitive control and: (AIM 1) volumetric/white matter integrity of these same brain regions and their connections; (AIM 2) the functional organization of cognitive control networks and task-related changes during control tasks; (AIM 3) specific behavioral evidence that cognitive control is affected. This approach will provide an unprecedented level of precision for investigating such relationships. If successful, this research will demonstrate early, pre-clinical links between arterial dysfunction and the emergence of brain and cognitive problems, and will help devise strategies for possible individualized, precision-medicine-inspired interventions to stave off early phases of age-related cognitive decline and dementia.