Blaise deBonneval Frederick, B.S., Ph.D. - US grants

DESCRIPTION: (provided by applicant) This is a request for 5 years of funding through the "Mentored Quantitative Research Career Award" (K25) mechanism. The applicant, a biophysicist/electrical engineer, proposes a program of training in neuroscience and pharmacology. The long term goal of the applicant is to become an independent and interdisciplinary investigator, skilled in the application of magnetic resonance methods for the study of substance abuse research. The research component of this award will develop and improve functional magnetic resonance imaging (fMRI) techniques for the study of substance abuse and addiction in human subjects. These techniques will be applied to study the effects of cocaine administration in humans. Cocaine abuse is a serious public health problem having important psychiatric, medical, and drug abuse policy implications. Acute administration of cocaine alters central nervous system (CNS) neuronal activity and cerebral blood flow; chronic use of cocaine can lead to long term neuronal and behavioral changes, as well as to alterations in cerebral vascular function. fMRI uses blood oxygenation changes to estimate neuronal activity, with a temporal resolution of several seconds and spatial resolution of a few millimeters. However, signal to noise ratio (SNR) and temporal resolution limits put constraints on the parameters that can currently be measured in vivo. Three separate technical development efforts are proposed. First, a phased array echoplanar imaging system, optimized for the study of brain regions which may mediate the rewarding effects of cocaine, will be implemented on a 4 Tesla MR scanner. This system will significantly increase the SNR of fMRI, and allow the detection of cocaine-induced alterations in neuronal activity in ventral striatum, thalamus, and posterior neocortex in individual subjects. Second, a method for rapidly and simultaneously assessing the relative BOLD activation resulting from blue and red light will be developed with a time resolution of at least one multicolor measurement per minute to determine the relationship between cocaine's effects on color visual processing (a proxy for dopaminergic alterations) and activation in other brain regions. Third, a set of experimental studies will be conducted to determine the relationship between EEG alpha activity (a surrogate marker for drug-induced euphoria) and the BOLD photic response. This study may aid in the development of magnetic resonance methods for assessing EEG alpha activity, giving an objective measure of the euphorigenic effects of various drugs. The long term goals of this research are to provide a better understanding of the phenomenon of cocaine abuse so that better prevention and treatment strategies can be developed and evaluated.

[unreadable] DESCRIPTION (provided by applicant): This R21 application proposes to develop a novel way of measuring brain function after smoking marijuana that combines Functional Magnetic Resonance Imaging (fMRI) and Near Infrared Spectroscopy (NIRS). Background: Marijuana remains the most commonly used illicit drug in the U.S., but we do not to date understand the full spectrum of its reinforcing effects. Advanced brain imaging techniques such as PET, SPECT, EEG and MRI have been used to explore the acute and chronic effects of marijuana, but each of these techniques has limitations that preclude its use in some situations or populations. Recently, we have developed a device that allows individuals to smoke marijuana during functional magnetic resonance imaging (fMRI) and have successfully correlated fMRI data with subjective reports of behavioral states such as high, and physiological responses. The merger of fMRI with behavior during smoking is an important breakthrough in our knowledge of the spatial and temporal patterns of brain activity changes during marijuana use. This knowledge will be crucial for the development of rational and effective treatments for marijuana dependence. Significance: However, there are three important issues that need to be addressed to maximize the utility of fMRI.. First, perception of pleasurable drug effects is subjective, and is modulated by mood. Subjects must remain immobile in a confined space for up to two hours and these conditions can be unnatural for some people, and most likely affect their perception of what would otherwise be a rewarding experience. Second, BOLD fMRI only gives information about deoxy-hemoglobin changes, not changes in oxy-hemoglobin or blood flow. Third, a major confound in brain fMRI is distortion and signal loss around regions of discontinuous magnetic susceptibility, specifically air-tissue interfaces. Also, there is considerable motion artifact. NIRS offers an ideal companion method for studying frontal brain activity changes that addresses all of these concerns. NIRS is a method for making local measurements of cortical blood oxygenation and flow, which are closely coupled to neural activity. While its spatial resolution is lower than fMRI, and it is limited to regions near the cortical surface, its temporal resolution is significantly better than fMRI. These qualities make it well suited to enhancing the data acquired with fMRI. Specific Aims: In this proposal, we will: 1) develop and optimize an fMRI compatible depth sensitive NIRS imaging probe for the study of frontal areas; 2) Compare frontal activations measured concurrently during marijuana smoking using NIRS and BOLD fMRI, and 3) compare NIRS activation in response to marijuana smoking inside the fMRI scanner to activation in a natural setting. This study will pave the way for using brain imaging in vulnerable populations like children and pregnant women. This project aims to develop and validate an extremely safe, low-cost, non-invasive method for measuring the brain changes that occur during marijuana smoking. This study will pave the way for using brain imaging in vulnerable populations like children and pregnant women, and will provide a better understanding of the reinforcing effects of this drug. This understanding is a necessary step in developing strategies and therapies for reducing marijuana use and abuse. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This proposal is to fund a complete refurbishment of the McLean Hospital 4 Tesla Varian Whole Body Multinuclear Magnetic Resonance Imaging system. This instrument has been extremely productive since it was first installed in May, 2001 both as a development platform for new spectroscopy techniques, and as the means for applying these techniques in several thousand subjects for NIH funded projects. However, the rapid pace of technical development in the MR field means that recent advances in the field are difficult or impossible to implement on the current hardware. This is especially relevant as we are building a translational program at McLean that will partner the 4T with a new, 9.4T Varian animal scanner (currently being installed), where we expect to develop techniques that may be useful in humans. Our current 4T scanner, particularly the console hardware and user interface, once at the forefront of technology, has become dated. This has manifested itself in increasing unreliability and downtime, continued requirements for both extensive user training, and time-consuming interventions from staff physicists to repair and maintain the system. The proposed upgrade will replace the heart of the spectrometer;the signal generation, measurement, processing and interface components. The magnet, gradients, shim supply and power amplifiers, remain in excellent working order and will be retained. This offers a unique opportunity to acquire a state of the art MR spectrometer at a fraction of the cost of a new unit, by leveraging the value of the existing magnet and sitting infrastructure. Since 2001, there have been significant technical advances in all aspects of Varian's MR console hardware;digital radiofrequency receiver hardware gives much higher detection sensitivity of rare compounds, better time stability in long acquisitions, and sharper filtering with minimal phase roll, which significantly improves spectral quantitation. A new RF front end improves noise figure and enables more flexible transmit receive configurations. Parallel RF transmission and reception improves RF homogeneity, can reduce power deposition, and can increase SNR and speed image and MRSI acquisition through the use of phased array and SENSE techniques. Revised grounding topology further improves SNR. Finally, the new, faster workstation improves acquisition and processing efficiency. Relevance: The McLean 4T scanner is one of the leading sites in the US for performing multinuclear MR spectroscopy in humans;we routinely employ 1H, 31P, 7Li, 23Na, 19F and 13C spectroscopy to study a wide range of psychiatric and substance abuse disorders. Multinuclear MR spectroscopy is an extremely important tool for evaluating new therapies for these disorders;this upgrade will keep this scanner at the forefront of the field, and will open up new opportunities for rapidly translating discoveries made in other animals to humans. PUBLIC HEALTH RELEVANCE This proposal is to fund a complete refurbishment of the McLean Hospital 4 Tesla Varian Whole Body Multinuclear Magnetic Resonance Imaging system. This scanner is one of the leading sites in the United States for performing multinuclear MR spectroscopy in humans;we routinely employ 1H, 31P, 7Li, 23Na, 19F and 13C spectroscopy to study a wide range of psychiatric and substance abuse disorders. Multinuclear MR spectroscopy is an extremely important tool for evaluating new therapies for these disorders;this upgrade will keep this scanner at the forefront of the field, and will open up new opportunities for rapidly translating discoveries made in other animals to humans.

DESCRIPTION (provided by applicant): This R21 proposal will develop and validate a real-time near infrared spectroscopy (NIRS) imaging system that will allow subjects to monitor their own frontal brain activity, as it happens, in order to learn to modulate this activity. By modulating activity in frontal regions associated with drug craving and drug seeking behavior, subjects may be able to learn strategies to reduce drug craving a reduce the probability of relapse. Background: Biofeedback teaches individuals how to regulate autonomic bodily functions normally considered to be outside of the realm of conscious control by giving them immediate and continuous feedback reflecting the state of a process that is normally not perceptible to them. Neurofeedback is an extension of this concept where the quantity presented to the subject represents a measure of neural activity in a target brain region. Neurofeedback using EEG and real-time fMRI has shown utility in increasing attention, enhancing musicality, and improving mod, and modifying the subjective perception of pain. Real-time NIRS (rtNIRS) offers a potential alternative method for high-quality measurement of frontal cortical brain activity, an area important in decision-making processes having to do with drug craving and seeking, with good spatial localization, high temporal resolution, and simple acquisition hardware that is relatively portable and low-cost. Conscious control of brain activity in this region could blunt the drug craving that leads to relapse. Significance: Neurofeedback with rtNIRS has the potential to become a powerful tool for treatment of substance abuse and prevention of relapse. Real-time neurofeedback with rtfMRI has been shown to be effective in modulating a wide range of behaviors and perceptions. rtNIRS could potentially offer the benefits of neurofeedback at much lower cost and in a wider range of populations than rtfMRI. Specific Aims: 1) Develop an optical helmet optimized for real-time frontal lobe neurofeedback. The target design will provide good bilateral coverage of areas, and provide measurements of extracerebral blood flow to allow these signals to be modeled and removed during analysis;2) Implement a real-time NIRS processing chain. This aim will streamline the data recording and analysis process of our current NIRS system so that NIRS data will be preprocessed and analyzed for presentation to the subject with less than 1 second latency;3) Implement a feedback system to present brain activity data to the subject. In this aim we will evaluate candidate visual representations of neural activity for their ability to assist subject training 4) Investigate the feasibility of conscious control of brain activity in a specified frontal brain region with feedback consisting of real-time measures of regional activation. Frontal cortical executive whether neurofeedback alters performance on Go-NoGo and Balloon Analog Risk Tasks. Realtime NIRS will We will test provide a complementary methodology to real-time fMRI and EEG for modulating brain activity, as a step towards the goal of developing a novel treatment strategy to combat substance abuse and relapse. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop and test a real-time near infrared spectroscopic (NIRS) functional imaging system to allow subjects to directly monitor, and as a result modulate, their frontal brain activity. The data from this exploratory study will be used to develop a novel and potentially important tool for training subjects to reduce drug craving and drug seeking behaviors.

DESCRIPTION (provided by applicant): This R21 project will develop and validate a novel method of imaging hemodynamic parameters (CBV and CBF) in vivo, based on crossmodal processing of concurrently recorded fMRI and NIRS data using Regressor Interpolation at Progressive Time Delays (RIPTiDe). This new, non-invasive imaging technique allows the routine generation of quantitative CBF and CBV images simultaneously with BOLD imaging data, and avoids many pitfalls of existing methods (DSC MRI, ASL and VASO). Background: RIPTiDe imaging exploits the fact the NIRS and fMRI both measure blood oxygenation and concentration fluctuations, but share no instrumental noise mechanisms. Therefore the temporal crosscorrelation of the NIRS and BOLD data represents the strength and timing of the propagation of endogenous fluctuations in blood oxygenation and volume through the vasculature. We can quantify the amplitude and arrival time of these signals in single subjects during brief scans at high signal to noise(1), and have used this technique for filtering physiological noise from BOLD data (2), and measuring cerebrovascular reactivity to a breathhold challenge (3). Using existing biophysical models of the BOLD effect, we propose using this data to quantitatively estimate cerebral blood flow and volume at high spatial resolution. Measurements can be made concurrently with conventional fMRI acquisitions, and require no special fMRI acquisition sequences or parameters. Moreover, the near infrared acquisition hardware required for this type of measurement can in principal be quite inexpensive, making it practical to add it to existing MR scanners. We will reduce this measurement to practice, and compare its results and data quality to ASL and VASO. Significance: Simultaneously acquired fMRI/NIRS data processed using RIPTiDe allows us to isolate the contribution of hemodynamic fluctuations to the BOLD signal in every voxel. This permits significant reduction in the physiological noise in the BOLD data, and simultaneously yields an estimate of blood flow and volume at every location. This allows truly concurrent acquisition of high quality BOLD, CBV, and CBF information. Specific Aims: 1) Compare data quality obtained using NIRS from four different recording locations. The location of NIRS recording affects the purity of the measured hemodynamic signal. RIPTiDe images will be calculated using NIRS data from four probe locations, and compared to choose a standard recording location; 2) Evaluate the use of RIPTiDe data as input to the Balloon Model to generate quantitative estimates of blood flow and volume. We will use the RIPTiDe data (optimally delayed NIRS [HbR] and [tHb], and BOLD) as inputs to the balloon model, calculate CBV and CBF, and compare results and SNR/unit time with ASL and VASO; 3) Implement a RIPTiDe processing package. This aim will develop a streamlined data recording and analysis suite to simplify the use of RIPTiDe data, and allow other researchers to use this method. PUBLIC HEALTH RELEVANCE: The goal of this project is to improve existing multimodal processing of concurrently acquired NIRS and fMRI data to yield quantitative cerebral hemodynamic data (cerebral blood volume, cerebral blood flow, and mean transit time). The technique will be tested on 20 healthy subjects, and compared with arterial spin labeling and vascular space occupancy measurements.

DESCRIPTION (provided by applicant): We propose to advance the use and interpretation of near-infrared spectroscopy (NIRS) technology by determining the faithfulness to which NIRS localizes patterns of blood flow relevant to addiction-related processes. Importantly, these NIRS signals will be simultaneously collected with behavioral measures of addiction (e.g., self-administration) in real-time. Currently, the use of functional magnetic resonance (fMRI) for the study of small mammals is difficult and relatively impractical for the majority of researchers. Our goal is to provide a poor man's functional imaging device that will be available for a modest cost and is readily accessible and easy to implement. Simply stated, our intent is to rapidly increase our knowledge base about blood flow changes in animals that could be readily translated to understanding human processing of drug-related information. In the proposed research, we will use a multi-faceted approach including NIRS, MFI, and intravenous self- administration of cocaine to determine whether localized assessment with NIRS is a useful alternative to fMRI to determine changes in blood flow. We will extend the utility of the NIRS approach to freely moving animals that are actively self-administering cocaine. Both the significance and innovation of this approach is relevant for the CEBRA due to the development of innovative technology to rapidly advance our understanding of blood flow change in animal models. Aims Proposed: * Specific Aim 1. To establish the similarities in blood flow changes detected by fMRI and NIRS. * Specific Aim II: To determine whether we can use NIRS to monitor neuronal activity in real-time in freely moving animals.

Summary Cerebrovascular reactivity (CVR) is clinical measure of cerebrovascular function influenced by micro- and macrovascular effects including delay in blood arrival time, delay in tissue reponse, and chronic vasodilation. Individually and simultaneously determing blood flow delay, CVR magnitude and CVR delay using time delay analysis methods we have developed will yield much richer and more specific information about underlying vascular pathology than is currently available. In healthy tissue, vasodilation adjusts vessels' resistance to flow, and modulates cerebral perfusion in response to changing demands for oxygen and nutrients; this ability is reduced or absent in many forms of cerebrovascular pathology. Cerebrovascular reactivity (CVR), and the related quantity cerebrovascular reserve, are measures of brain blood vessels' capacity for vasodilation, which may offer useful clinical information in patients at risk for cerebral ischemia associated with chronic stenosis or occlusion of cerebral blood vessels. Traditional methods of CVR analysis, which correlate a modified schedule of CO2 changes in inhaled gases voxelwise with BOLD fMRI signal, lead to systematic underestimation of CVR magnitude in regions where the response is delayed with respect to the gas administration schedule. We have validated a method to detect and quantify local delays in blood flow arrival, and to derive corrected CVR magnitude maps. Even after the true magnitude of the CVR is known, questions remain regarding whether the delay in CVR is due to delayed arrival of blood in the tissue of interest (upstream pathology), or delayed vasodilation in impaired tissue (local pathology), or a combination of both. Therefore, we propose to use both vasodilatory and nonvasodilatory gas manipulations in combination with near-infrared spectroscopy during fMRI imaging to evaluate each source of delay separately. This proposal capitalizes on the technical resources available at McLean Hospital / Harvard and the unique clinical resources available at the Vanderbilt University Medical Center to develop, implement, and evaluate a clinical protocol for the noninvasive assessment of not only true CVR magnitude, but also the individual contributors to CVR and blood circulation times as they relate to underlying circulatory physiology. We will first study 70 healthy control subjects between 20 and 70 years old with the calibrated CVR method to separately determine CVR magnitude and delay time (Aim 1), and separately evaluate two components of CVR delay: blood arrival time, and tissue reactivity time (Aim 2). We will then perform the same measures in a population of 30 patients with intracranial atherosclerotic stenosis, and 15 age-matched controls, to test the hypothesis that blood arrival time delay is increased and CVR magnitude is decreased in areas affected by stenosis (Aim 3). Previous work strongly suggests that the relative contribution of these two factors will help differentiate different types of pathology with different etiologies.