Gabriele Gratton - US grants

Understanding of the functioning of the human brain would clearly benefit from physiological techniques able to provide dynamic maps of activity. Current electrophysiological and hemodynamic methods provide data with either good spatial or temporal resolution, but not both. Our preliminary studies indicate that non-invasive optical methods can provide a unique combination of spatial and temporal resolution that could be used to derive dynamic maps of brain activity. In addition, these techniques are compatible with other methods. However, our understanding of non-invasive optical methods is still incomplete. The specific purposes of the present project are: (a) to extend the preliminary findings about the sensitivity and spatial and temporal resolution of optical methods, (b) to provide initial data about the basic mechanisms underlying the optical signals, (c) to assess the ability of optical methods to provide depth information, and (d) to elucidate further the relationship between optical and electrical measures. The project will involve direct comparison of electrophysiological and optical data simultaneously recorded from the heads of normal human subjects with comparable spatial and temporal sampling. Structural, and in some cases functional, magnetic resonance data will also be acquired from the same subjects. The desired outcome is the development of tools for generating detailed spatio- temporal maps of brain activity during sensory, motor, and cognitive tasks. Possible future extensions include the application of the combined optical-electrophysiological approach to the study of the neurophysiology of cognition and neurological and psychiatric syndromes.

DESCRIPTION (provided by applicant): The purpose of this proposal (responding to RFA EB-005-001) is to pursue the integrated development of a functional brain imaging approach based on the fast optical signal. This signal is characterized by rapid changes in cortical transparency occurring immediately after stimulation and simultaneous with electrophysiological measures of neuronal activity. The current proposal unites three groups (at the University of Illinois at Urbana-Champaign - UIUC, University of California-Irvine - UCI, and Pennsylvania State University - PSU) that have played a critical role in the discovery and initial observations of the fast optical signal in humans. The main goals of the proposed research, covering five of the six goals stated in the RFA, are: (a) To investigate the biophysical phenomena underlying the fast optical signals through a combination of simulation studies and measurements conducted on animal models, comparing fast optical signals and electrophysiological measures of neuronal activity. (RFA GOALS#1&2) (b) To examine the relationship between intracranial changes and optical parameters recorded at the scalp and used for detecting the fast optical signals in humans. This will involve recording of fast optical signals in humans as well as Monte Carlo simulation. (RFA GOALS#4&6). (c) To develop and validate mapping and other analytic tools for the 3-D reconstruction of cortical activity based on realistic head models, through the comparison of optical and fMRI data (RFA GOAL#5). (d) To significantly improve the signal-to-noise ratio (S/N) of optical signals through radical modifications of the current instrumental designs and improvements in recording and filtering methods. (RFA GOAL#6).

DESCRIPTION (provided by applicant This application is in response to "PAR-09-118 - Recovery Act Limited Competition: High-End Instrumentation Grant Program (S10)" With this application we request funding for the acquisition of a frequency-domain diffusive optical imaging (DOT) system for the Biomedical Imaging Center at the University of Illinois. DOT is an emerging technology that enables the non- invasive measurement of a number of physiological parameters of the brain with a combination of temporal (<50 ms) and spatial (<1 cm) resolution (when high-density recording and mapping techniques are used). Specifically, funds are requested for the acquisition of a 128-source, 24-detector Dual-Imagent system produced by ISS Inc., located in Champaign, Illinois, capable of recording up to 1,536 channels (source-detector combinations). The system will come equipped with 10 meter-long, non-magnetic fibers that will allow its use both inside and outside the 3T full-body Siemens TRIO magnetic resonance (MR) scanner that will be installed at the Biomedical Imaging Center (BIC) in July, 2009. Among the physiological variables that can be assessed using the Dual-Imagent are the relative and absolute concentration of oxy- and deoxy-hemoglobin, as well as total hemoglobin and saturation level in brain tissue, pulse parameters associated with arterial elasticity and stiffness, and scattering changes associated with neuronal activity (fast optical signal, FOS, and the event-related optical signal, EROS). In addition, the system bundle will also include an optical 3-D digitizing device for accurate co-registration of the functional optical data with structural MR images. Our group, and in particular the principal investigator, has extensive experience with the use of optical instruments, and has played a critical role in the development of fast optical signals. If the project is funded, BIC will hire an experienced scientist (Dr. Maclin) at 50 percent to provide support for users of the machine. The acquisition of the new system will allow a large number of investigators, most of whom are recipient of R01 NIH funding, to perform optical research, which will greatly enhance their research programs. A list of major and minor users, and descriptions of the way in which they will use the new optical system, are provided with this application.

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.