Xiaoping Hu, Ph.D. - US grants

This is a SGER proposal whose objectives are to (a), investigate, both theoretically and experimentally, a new, fast high resolution Magnetic Resonance Imaging (MRI) technique based on the discrete wavelet transform, and (b), establish (at least, experimentally) its feasibility and superiority over contemporary MRI approaches. The anticipated advantages of the proposed new approach include a dramatic reduction in the overall imaging time with no reduction in resolution or contrast.

technology /technique development; male; female; magnetic resonance imaging; human subject; nuclear magnetic resonance spectroscopy; biomedical resource;

DESCRIPTION: Localization of epileptogenic zones in epilepsy patients is a prerequisite for the surgical relief of medically refractory partial seizures. In patients with non-lesional extratemporal epilepsy (ETE), localization of seizure foci is usually difficult with traditional non-invasive methods such as scalp electroencephalography, positron emission tomography, single photon emission computed tomography, magnetic resonance imaging and neurological testing. The long-term goal of the proposed study is to establish proton metabolite mapping with chemical shift imaging as a means of localization for seizure foci in ETE patients. To this end, a number of difficulties will need to be tackled including signal contamination from subcutaneous lipid, partial volume effects and difficulty in accessing patient data without absolute quantification of the metabolites. The specific aims of this project have not changed except for the specific inclusion of the patient studies. They are: 1) to develop a new technique for obtaining proton chemical shift images of the head without signal contamination from the subcutaneous lipid, 2) to obtain partial volume corrected measurements of relative metabolite levels in normal volunteers in order to establish a reference data base of metabolites of relevance, 3) to develop and validate an adaptive normalization technique that takes into account variations and relative metabolite levels in normal controls and in individual subject anatomy and, 4) to validate the sensitivity of the proposed development in a population of patients with known seizure foci. This work will be carried out on a 1.5 Tesla whole body magnetic resonance imaging/spectroscopy system. For specific aim 1, improvements will be implemented to the 2DCSI spin warp technique. This will involve the development of echoplaner spectroscopic imaging combined with a conventional CSI sequence to cover k-space in a hybrid fashion. For specific aim 2, correction of the partial volume effect will be approached utilizing segmentation of anatomic images. The first component of the correction will be incorporation of partial volume effect in the derivation of the tissue specific relative metabolite levels in the brain. Secondly, correction for individual anatomy in the normalization of the patient data will be attempted. Over the three year period of the proposal the sequence development and validation will be completed in the first year. Development and implementation of processing algorithms will start concurrently with the sequence development and will be validated with experimental data in the early part of the second year. Patient studies will be conducted in the second and third years of the proposal to validate the technical developments and establish clinical protocols suitable for more extensive studies in the future.

technology /technique development; male; female; mental disorders; magnetic resonance imaging; nervous system; human subject; biomedical resource;

Temporal studies were performed both to understand spatiotemporal characteristics of signal in fMRI images and to examine temporal evolution of neuronal processing. In a time-resolved study of the visual system, the nature of the spatiotemporal characteristics of functional magnetic resonance imaging was examined using sophisticated mathematical tools. This study revealed a rich spatiotemporal structure in the stimulus related changes even for a very simple visual stimulation protocol, suggesting that distinct structures respond differently to the stimulus. In addition to revealing the temporal characteristics, this work also presented a number of novel mathematical approaches for processing the data, including a novel approach for removing gross motion artifact.

9907842


Kamil Ugurbil

This grant involves funds for the purchase of a 7 Tesla/90cm bore NMR imaging/spectroscopy instrument for the Center for Magnetic Resonance Research (CMRR) at the University of Minnesota. Only recently has it been possible to develop the necessary instrumentation and methodology, explore the potential and establish the advantages of the higher fields to extract complementary functional and biochemical information. A significant part of that work was realized at the CMRR. The 7T/90 system will enable a major lead in these developments and provide a mechanism by which this unique instrumentation, spin-physics methodology and expertise are available to researchers in the USA and elsewhere.

Unraveling the mysteries of the human brain represents one of the great challenges of modern biology. Recently, developed functional magnetic resonance imaging (fMRI) has provided a unique capability towards meeting this challenge. Further developments to improve sensitivity, spatial specificity and spatial resolution and extend the methodology to temporally resolved true single event related studies require higher neuronal activation and significant increases in the magnitude of the inherently weak signal changes that are used in fMRI. In going to 7 Tesla, these combined gains are expected to catapult this methodology to a level that is significantly beyond what is currently available. Equally important are recent efforts relying on detection of key intracellular bioenergetics and neuronal activity. However, additional gains in sensitivity and spectral resolution available at 7T are needed to make a significant impact on the biological problem.

DESCRIPTION (Adapted From The Applicant's Abstract): Functional magnetic resonance imaging (fMRI) is becoming a widely accepted methodology for studying brain function in both normal and diseased states. While many technical advances have been made in fMRI in the past several years, there are still technical limitations associated with the methodology. One aspect of fMRI that calls for further research is data processing. To date, the majority of the approaches for extracting signal change related to neuronal activity from MRI data rely on some prior knowledge of the fMRI response. These approaches are inadequate for application where the fMRI response is not known a priori and/or complex. Although model-free approaches have been previously introduced, further development is needed to make them robust and suitable for routine use. The goal of this project is to explore a new clustering approach based on self-organizing map (SOM) algorithms for identifying and detecting neural activity related responses in fMRI data. Specifically, we will 1) incorporate pixel connectivity in the SOM method, 2) develop statistical method(s) for optimally merging nodes in the SOM and testing the significance of the resultant clusters using approaches analogous to analysis of variance, and 3) validate the proposed approach with experimental data from paradigms that call for model free analysis methods. the success of this project will substantially expand the applications of fMRI by providing the means for detecting novel responses and permitting the use of flexible paradigm designs.

Echo-planar imaging (EPI) is sensitive to magnetic field inhomogeneities which lead to signal loss and geometric distortions of the image. The magnetic field inhomogeneities induced due to susceptibility differences, as encountered in the human body, increase with the magnetic field strength. Thus, it is a challenge to implement high resolution EPI techniques on high magnetic field systems. Furthermore, in EPI images, each k-space line has different dephasing in the phase-encoding direction if flow is present, causing artifacts in the phase-encoding direction. In the last grant period, we developed a new phase-encoded referencing scheme for EPI and demonstrated that the new referencing scheme virtually eliminates N/2 ghosts despite the strong field inhomogeneity present at high fields. The image distortion that may arise from Bo inhomogeneity in EPI as well as other ultrafast imaging sequences was also addressed in the last year with a new technique for correction such image degradation.

Mechanistic issues in BOLD based fMRI were further examined by comparing BOLD images with perfusion change measurements, demonstrating that in gray matter areas in the visual cortex, absolute and relative CBF changes in humans during photic stimulation were 31 1 11 SD ml/100 g tissue/min and 43 1 16 SD% (n = 12), respectively, while the relative oxygen consumption change was close to zero. These findings were in agreement with previous results using positron emission tomography.

We used high-temporal resolution echo-planar imaging (TR=100ms) to characterize the time-course of the BOLD signal during the initial stimulus onset. This study clearly demonstrated the existence of a negative BOLD response during first 2-4s of the stimulus onset, in total agreement with the results reported by the optical imaging studies. In a more recent study, by taking advantage of the retrospective correction technique for removing physiological noise, we have conducted a more elaborate study of the early response, clearly demonstrating the ability of initial response mapping in individual subjects.

DESCRIPTION (Adapted from Applicant's Abstract): In the last few years, a significant new development in fMRI is the introduction of event-related techniques that are also known as single-trial or time-resolved approaches. By providing temporally-resolved fMRI response evoked by individual events, event-related fMRI can elucidate temporal profiles of events taking place in the neural circuit and provide trial-specific information. Therefore, event-related techniques represent a major breakthrough in fMRI, hold a great potential for imaging the function of brain with an added dimension and have become widely utilized since its introduction. However, since event-related studies differ from those based on the traditional block design, and the associated temporal response is often small and unknown a priori, technical difficulties are still present. The first part of this application is thus aimed at developing a set of tools to improve event-related fMRI. Specifically, the applicants propose to develop and validate: 1) methods for improving the signal-to-noise ratio in event-related fMRI data; 2) methods for time course feature extraction and activation identification in event-related fMRI; and 3) analysis techniques for characterizing event-related fMRI time courses. In addition, the propose to also develop 4) adaptive imaging techniques for event-related fMR] with improved temporal resolution. After their development and validation, the techniques will be further demonstrated with two cognitive tasks that have not been previously examined with event-related fMRI. The first paradigm is use-word generation task that was previously demonstrated by PET studies to involve spatially separate areas that were shown by ERP to exhibit unique temporal relationships. The applicants propose to use event-related fMRI to investigate these areas and compare the timing derived from event-related fMRI with that reported by ERP to test the hypothesis that event-related fMRI can ascertain temporal differences in neuronal response to the use-word generation in the domain of hundreds of milliseconds. The second task to be studied is a delayed non-match to sample (DNMS) task which is thought to involve both cortical areas and medial temporal lobe, in a temporally differential manner. Specifically, the applicants propose to examine a modified DNMS paradigm using event-related fMRI to ascertain the activation in areas involved in the task and to elucidate temporal profiles of the activity in these areas. The hypotheses are that the medial temporal lobe is involved, differences exist in activation profiles of different areas, and the differences can be elucidated with event-related fMRI to aid in the understanding of the roles played by these areas.

DESCRIPTION (provided by applicant): Prenatal cocaine exposure (CE) has been a major public health concern since the epidemic of use that began in the 1980s. A number of studies have examined the physical, neurodevelopmental, and psychosocial effects of parental cocaine abuse and prenatal cocaine exposure in infants and young children but provided limited understanding of the neurobiological basis and neurodevelopmental effects. Recent advances in neuroimaging methods have made it possible to examine directly and noninvasively the functional neuroanatomy and connectivity, making them ideally suited for investigating the neurobiology and developmental effects of prenatal CE. The overall goal of this project is to apply MRI based neuroimaging methods, in conjunction with neurobehavioral testing, to study the neurodevelopmental effects of prenatal CE during adolescence and to elucidate neurobiological basis of the effect of prenatal CE. The proposed imaging study will focus on arousal and attention regulation, the neuropsycological functions which have been implicated most reliably in most studies of prenatal CE, the brain circuitry involved in these functions, and developmental effects on these brain circuitry during puberty, which, as a period of rapid reorganization, is ideal for the assessment of delays or divergences in development as a result of prenatal CE. We hypothesize that (1) using MRI, developmental change in structure and function will be evident in youth assessed over a 6 year period from 12 to 18 with measures of brain activity, neuroanatomic connectivity, and functional connectivity; (2) adolescents with prenatal cocaine exposure will exhibit deficit in arousal and attention regulation when compared to SES-matched controls, and these deficits will be more evident in situations involving stress than at "baseline" and will be measurable using MRI techniques as well as behavioral assessment of functioning; and (3)There will be correlations between MRI and behavioral measures. To test these hypotheses, the specific aims are (1) to compare functional anatomy of CE subjects and SES- and age matched controls at 3 age levels, 12, 15 and 18-years, to identify the patterns of developmental characteristic of each group; (2) to assess possible alterations in the neuroanatomic connectivity in and between areas serving the function of arousal and attention regulation in these groups using diffusion tensor imaging; (3) to assess functional connectivity in neural circuits in these groups; and (4) to assess behavior and adaptive functioning in these groups and correlate these outcomes with MRI findings. We believe the studies proposed in this project, the first to apply neuroimaging methods to this population, will allow us to ascertain possible alterations in the brain as a result of prenatal CE and measure any developmental effects on the brain during puberty.

DESCRIPTION (provided by applicant): Despite the maturing of the methodology of functional magnetic resonance imaging (fMRI) based on the endogenous blood oxygenation level dependent (BOLD) contrast, advances are still being made in a number of aspects, furthering the application and utility of fMRI. This proposal is a competitive renewal of a currently funded project, in which we focused our research on methodological issues in event-related fMRI and characterization of the BOLD response, particularly at very high magnetic fields, along with applications to studying brain cognition. Our effort has resulted in a number of new techniques for data acquisition and analysis, a further understanding of the BOLD response and a contribution to the understanding of brain cognition. In this renewal, we propose to further enhance BOLD based functional imaging by developing new imaging techniques. Furthermore, because recent work has illustrated the feasibility and utility of detecting brain connectivity and the potential of combining connectivity measures with fMRI, we will investigate methods for detecting brain connectivity and combining these measures with BOLD imaging. With this in mind, the first 2 specific aims of this application will focus on the development of approaches for improved BOLD imaging and the development of new methods for measuring anatomic and functional connectivity. Along with these methodological developments, we will demonstrate the utility of these functional and connectivity measures by applying them to study the disruption of language related brain network in autism. The accomplishment of these aims will lead to methodological advances, better characterization of connectivity measures, and better understanding of neurobiological basis of autism and fetal alcohol syndrome. We believe the proposed work is both innovative and scientifically significant.

DESCRIPTION (provided by applicant): Prenatal cocaine exposure (CE) has been a major public health concern since the epidemic of use that began in the 1980s. A number of studies have examined the physical, neurodevelopmental, and psychosocial effects of parental cocaine abuse and prenatal cocaine exposure in infants and young children but provided limited understanding of the neurobiological basis and neurodevelopmental effects. Recent advances in neuroimaging methods have made it possible to examine directly and noninvasively the functional neuroanatomy and connectivity, making them ideally suited for investigating the neurobiology and developmental effects of prenatal CE. The overall goal of this project is to apply MRI based neuroimaging methods, in conjunction with neurobehavioral testing, to study the neurodevelopmental effects of prenatal CE during adolescence and to elucidate neurobiological basis of the effect of prenatal CE. The proposed imaging study will focus on arousal and attention regulation, the neuropsycological functions which have been implicated most reliably in most studies of prenatal CE, the brain circuitry involved in these functions, and developmental effects on these brain circuitry during puberty, which, as a period of rapid reorganization, is ideal for the assessment of delays or divergences in development as a result of prenatal CE. We hypothesize that (1) using MRI, developmental change in structure and function will be evident in youth assessed over a 6 year period from 12 to 18 with measures of brain activity, neuroanatomic connectivity, and functional connectivity; (2) adolescents with prenatal cocaine exposure will exhibit deficit in arousal and attention regulation when compared to SES-matched controls, and these deficits will be more evident in situations involving stress than at "baseline" and will be measurable using MRI techniques as well as behavioral assessment of functioning; and (3)There will be correlations between MRI and behavioral measures. To test these hypotheses, the specific aims are (1) to compare functional anatomy of CE subjects and SES- and age matched controls at 3 age levels, 12, 15 and 18-years, to identify the patterns of developmental characteristic of each group; (2) to assess possible alterations in the neuroanatomic connectivity in and between areas serving the function of arousal and attention regulation in these groups using diffusion tensor imaging; (3) to assess functional connectivity in neural circuits in these groups; and (4) to assess behavior and adaptive functioning in these groups and correlate these outcomes with MRI findings. We believe the studies proposed in this project, the first to apply neuroimaging methods to this population, will allow us to ascertain possible alterations in the brain as a result of prenatal CE and measure any developmental effects on the brain during puberty.

In creating the Emory Molecular and Translational Imaging Center (EMTIC), we have built upon a uniquely supportive Atlanta biomedical environment, a flourishing imaging research community across Emory University and the Georgia Institute of Technology (Georgia Tech), and remarkable growth of the Winship Cancer Institute. The vision and mission for EMTIC is a cross-disciplinary scientific, administrative, and educational network that encompasses imaging scientists and basic and clinician scientists working in areas vital to cancer diagnosis and therapeutics. As conceived, EMTIC is the multi-faceted connector that joins disciplines to accelerate innovative methodological developments and foster their rapid clinical translation. Vital to this mission, EMTIC is closely .aligned with strategic and transforming investments in imaging technology, biomarker development, predictive and personalized medicine, and nanotechnology based at Emory and Georgia Tech. Progress in the development and validation of molecular imaging cancer biomarkers will be founded in a structure of three major Research Projects, four Specialized Resources (Cores), investment in Developmental Funds to support Pilot projects, and a focused Career Development Component. The Research Projects include (Project #1) a translational study of prostate cancer patients using [[18]F]FACBC, an amino acid transporter ligand developed at Emory and an example of the bench-to-bedside capabilities of our investigative team. Project #2 will develop and validate selective chemokine PET markers in head and neck cancer. In Project #3 we will evaluate a unique target-specific molecular MRI probe in a breast cancer animal model. Project #4 tests a novel near-infrared (NIR) fluorescent dye in prostate cancer. Specialized Resources for Imaging (Core A), Tracer Development (Core B), Biostatistics, Modeling, and Data Management (Core C), and Animals, Pathology, and Tumor Models (Core D) will provide support for the Research Projects as well as Year 1 and future Pilot Projects. EMTIC will also provide an ideal structure for support of an integrated Career Development Program to equip the future imaging scientist with the interdisciplinary technical and translational skills to specialize in cellular and molecular imaging for cancer care.

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is the most common primary brain tumor and is uniformly fatal despite aggressive surgical and adjuvant therapy. Since survival is short, it is critical to determine the value of therapy early during treatment. Improved early predictive assessment would allow neuro-oncologists to adjust or change treatment sooner to maximize use of the most effective therapy. During carcinogenesis, tumor suppressor genes can be silenced by aberrant histone deacetylation. This epigenetic modification has become an important target for tumor therapy. Suberoylanilide hydroxamic acid (SAHA) is an orally active, potent inhibitor of histone deacetylase (HDAC) activity. Clinical effects may include tumor control and cerebral biochemical alterations that may improve mood, correcting the depressive symptoms experienced by many of these patients. Clinical evaluation of SAHA in recurrent GBM is currently ongoing within the NCI-funded Adult Brain Tumor Consortium (ABTC) because of the promising preclinical results in malignant gliomas. In addition, a phase I evaluation in newly diagnosed GBM in combination with temozolomide and radiation therapy has just been opened by this group. The lack of reliable biomarkers to predict early response severely hampers the treatment of GBM tumor patients with HDAC inhibitors. Frequent histological evaluation is impractical for GBM due to the risks of invasive biopsies and unreliable endpoints. Another problem is that response to SAHA therapy is associated with tumor redifferentiation/cytostasis rather than tumor size reduction, limiting the use of traditional imaging methods. We propose to fill this void by optimizing an MRS method to pharmacodynamically assess biomarkers noninvasively and longitudinally. In this manner, we evaluate the efficacy of drug delivery and therapeutic effect early in the course of the treatment. Here our objective is to develop an MRS-based tool to aid clinicians in the early determination of the value of SAHA when administered to recurrent GBM patients treated with SAHA in combination with temozolomide, thereby identifying patients most likely to benefit. In addition, we will determine whether reduced inositol and NAA are reliable biomarkers of altered mood or depression in GBM patients, which may alleviated with SAHA treatment. Therefore, we plan to assess for potential improvement in the mood of recurrent GBM patients by correlating MRS data with a psychiatric evaluation. Establishing reliable MRS biomarkers to assess early response would clearly be of value in personalizing the management of glioblastoma patients by allowing clinicians to adjust the dose of SAHA treatment or seek alternative treatment. The ability to do this would be a highly innovative use of established technology (MRS) that would be readily implemented at most institutions. Importantly, our MRS-based tool will assess the restoration of normal brain metabolism, and indirectly monitor the subject's quality of life. PUBLIC HEALTH RELEVANCE: During carcinogenesis, tumor-suppressor genes can be silenced by aberrant histone deacetylation. This epigenetic modification has become an important target for tumor therapy. Vorinostat (SAHA, Zolinza;Merck &Co., Inc., Whitehouse Station, NJ) is an orally active, potent inhibitor of aberrant histone deacetylation activity that is currently being evaluated in glioblastoma patients. In this study, we will establish an important clinical tool to predict therapeutic response soon after treatment initiation. Our MRS- based tool will aid clinicians in early modification of SAHA treatment or in seeking alternative treatments in those with glioblastoma.

DESCRIPTION (provided by applicant): This application is in response to the PA-10-067 (Research Project Grant (Parent R01)). Problem statement: Recent neuroimaging studies in the literature, including our own ones, have shown that several brain networks, including arousal regulation, working memory, language, executive function, attention, and vision systems are altered in prenatal cocaine exposure (PCE) affected brains. However, the alterations of structural and functional connectivities in large-scale brain networks and the alterations of structural brain architecture in PCE affected adolescents are largely unknown. The major barrier to the quantitative assessments of large-scale brain connectivities in PCE adolescents and controls is the critical lack of dense brain landmarks that are consistent across different brains and can serve as common network nodes for connectivity mapping. Approaches: Recently, we created and validated a transformative data-driven approach that discovered a dense map of 358 consistent brain landmarks, called Dense Individualized and Common Connectivity-based Cortical Landmarks (DICCCOL), in healthy young adult brains, each of which is defined by consistent white matter fiber connectivity pattern derived from diffusion tensor imaging (DTI) data. Our validation results have shown that these 358 DTI-derived DICCCOL landmarks are strikingly reproducible in separate datasets, have meaningful and accurate functional localizations, and possess automatically-established cross-subjects correspondences. Importantly, these 358 brain landmarks can be accurately and efficiently predicted in a new, single brain with DTI data. Therefore, this set of 358 dense landmarks offers common network nodes for large-scale structural and functional connectivities assessments. In this project, we propose to apply our DICCCOL models and their prediction framework on existing Emory PCE/control datasets and assess large-scale connectivities in PCE affected adolescents. Significance: 1) The discovered common DICCCOL map, together with the consistent structural connection patterns, can be considered and used as the next-generation brain atlas, which will have much finer granularity and better functional homogeneity than the Brodmann brain atlas that has been used for over 100 years. 2) The dissemination of the DICCCOL prediction framework based on the open source platform of Insight Toolkit (ITK) and the DICCCOL map will contribute to numerous applications in brain imaging that rely on accurate localization of brain ROIs. 3) Connectivity alterations in large-scale brain networks of DICCCOL landmarks in PCE are largely unknown. This knowledge gap will be significantly bridged in this project by assessing large-scale networks in multimodal DTI and resting state fMRI datasets of PCE/control brains. PUBLIC HEALTH RELEVANCE: Briefly, this project aims to apply UGA Dense Individualized and Common Connectivity-based Cortical Landmarks (DICCCOL) models and landmark prediction framework on existing Emory prenatal cocaine exposure (PCE)/control datasets and assess large-scale connectivities in PCE adolescents. This project aims to predict DICCCOL maps in PCE/controls, discover common DICCCOL maps in three populations and assess large-scale structural connectivities in PCE/controls, and assess large-scale functional connectivities in PCE/controls. The outcome will be novel elucidations of PCE's teratogenic effects on widespread connectivity alterations and a collection of connectivity-based markers that are predictive of PCE clinical and behavior measurements.

DESCRIPTION (provided by applicant): This application seeks funding to upgrade our 3 Tesla whole body research MRI scanner which is currently fully utilized by projects relying on in vivo magnetic resonance imaging and spectroscopy at Emory University. The 3 Tesla scanner targeted for the requested upgrade is a 10-year-old Siemens Trio and is no longer state-of-the-art, particularly in terms of its multichannel receiving capability and associated RF coil. The upgrade is critically needed for us to provide the state-of-the-art in vivo imaging and spectroscopy capabilities, particularly for achieving the best data acquisition speed and data quality. In addition, the upgrade will provide us with latest sequences and software tools available from the vendor to maximize the usage of the scanner. Overall, the upgrade will significantly enhance Emory's federally funded research projects currently conducted on the scanner by 7 major users and a dozen minor users.

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common primary brain tumor and is uniformly fatal. During carcinogenesis, tumor suppressor genes are silenced by aberrant histone deacetylase (HDAC) activity. Reversing this modification has become a goal for tumor therapy. Suberoylanilide hydroxamic acid (SAHA) is an orally-active potent inhibitor of HDAC. This agent may not only help control tumors but also alter cerebral biochemistry to improve depressive symptoms afflicting many GBM patients. An NCI-funded multi-institutional trial for GBM combining SAHA with standard chemoradiation is scheduled to open soon. However, the lack of reliable biomarkers to predict early response severely hampers the treatment of GBM patients with HDAC inhibitors. Magnetic resonance imaging (MRI) is the standard tool for monitoring therapeutic response in GBMs. Although useful, conventional MRI has shortcomings including difficulty at distinguishing true tumor progression from pseudo-progression that is often seen soon after completion of chemoradiation. MRI may also not be ideal for evaluating new therapies, many of which help only a subset of patients. For GBMs, therapeutic response is mainly evaluated by assessing for tumor changes on conventional MRIs, since repeat surgical biopsy is too invasive and may be prone to sampling error. However, this is not ideal for evaluating response to SAHA since our preliminary data indicate that drug response is associated with redifferentiation rather than killing/shrinking tumors, which may normalize cancer cell metabolism. While conventional MRI detects tumor size and location, it cannot detect this type of normalization. We propose to fill this void by using MR spectroscopic imaging (MRSI), which uses special techniques in an MRI scanner to measure the metabolism of cancer cells as well as normal brain. While MRSI is not new, it has not gained widespread clinical use due to poor resolution, long scan times, and difficulty integrating with other types of brain scans. We propose to implement state-of-art MRSI technology that can rapidly generate metabolite maps of the entire brain coupled with introduction of an imaging registration/analysis program that combines MRSI data with other imaging studies in a clinically useful fashion. Our long-term goal is to develop MRSI into a practical clinical tool that can be readily implemented at most institutions. The establishment of reliable MRSI metabolic biomarkers to assess early response would be of great value in developing new treatments, especially those such as SAHA which do not work by simply killing cells. By allowing clinicians to detect normalization of cancer metabolism in as little as one week of therapy, patients destined to benefit from treatment may be reassured, while those not showing a metabolic response can be switched from an ineffective treatment without further wasting of time. This would clearly be a highly innovative use of MRSI. Importantly, in addition to monitoring tumor response to SAHA therapy, our MRSI-based tool will allow assessment of the biochemical content of normal brain, and may thus indirectly monitor the subject's quality-of-life.

This interdisciplinary research project will examine how language and technology, two defining human characteristics, are related to one another. The project will place emphasis on the development of human technology from early evolutionary transitions, such as stone tool-making and expansions of diets and habitats, to more recent transformations, such as agricultural, industrial, and information revolutions, in order to enhance basic understanding of these patterns of ever accelerating change, including the origins of language. The investigators will test the hypothesis that language is a special case of a more general capacity for complex, hierarchically structured, goal-oriented behavior evident in technology by integrating archaeological and neuroscience methods to investigate possible functional, anatomical, and evolutionary connections between language and tool-making. By investigating possible neural overlap between language and tool-making, the project will test major evolutionary hypotheses and promote integration between neuroscience and anthropology by developing new and broadly applicable methods for studying complex, naturalistic behavior. This project will pursue the hypothesis that hierarchical structure is a unifying principle in human cognition, crossing behavioral domains that are traditionally conceived as distinct. Project findings will have the potential to powerfully impact perceptions of the nature and origins of human intelligence.

To address questions regarding how language and technology are related to each other, this project will focus on the evolutionarily relevant, archaeologically visible behavior of stone tool-making. Louis Leakey commented that stone tools represent a form of "fossilised behavior" that can be used to make inferences about the evolution of human dexterity, cognition, and cultural transmission processes. The Early Stone Age accounts for roughly 90 percent of human prehistory, covering a time period from roughly 2.6 million years to 250,000 years before the present. The development of stone tools encompassed a technological progression from simple stone chips to skillfully shaped tools as well as a nearly three-fold increase in brain size. It is likely that many distinctive aspects of modern human brain structure and function evolved during this period. In order to study this proto-typical human technology using the modern methods of neuroscience, the investigators will teach experimental subjects to make Paleolithic tools. Cognitive, behavioral, and neurophysiological aspects of the learning process will be investigated using functional brain imaging, eye-tracking, the annotation and analysis of video-recorded tool-making action sequences, and archaeological analyses of the actual tools produced. Drawing on formal language theory, the researchers will develop new methods for describing the syntactic structure of these natural action sequences and for measuring their hierarchical complexity. Manual parsing of action sequences by expert observers will be compared with the data-driven segmentation of action streams based on the eye-movement patterns of research subjects in order to produce a robust consensus. These methods of "action syntax" analysis will be generalizable to other complex behaviors and will enable the direct comparison of hierarchical structure, information processing, and brain function across linguistic (story listening) and tool-making (action observation) behaviors in this study. This project is supported through the NSF Interdisciplinary Behavioral and Social Sciences Research (IBSS) competition.

? DESCRIPTION (provided by applicant): The current project will identify maturational changes in the infant brain that accompany important transitions in social behavior in the first 6 months o life. This work is motivated by a surprising feature of a recent study in which we identified the earliest known indicators of social disability in autism (Jones & Klin, Nature, 2013). The data falsified a prior hypothesis by revealing that eye-looking-a basic mechanism of social adaptive action in typical infants-was not immediately diminished in infants with autism; instead, infants with autism exhibited a slight but significant increase in eye-looking at 2 months, which then declined; in contrast, typical infants exhibited a relative low point in eye-looking at 2 months, which then increased. The timing of this difference highlights a narrow developmental window, around month-2, that spans an important period of dynamic transition in typical infants. At approximately 4-6 weeks, reflex-like neonatal predispositions-including among others: non-social, endogenous smiling1, 2; reflexive imitation3-5; and reflexive attention to faces6-decline. This decline is followed by major changes in infant behavior: after month 2, infants begin to engage in contingent social interaction: they increase time spent looking at others' eyes10,11 and produce socially-elicited smiles during interaction with caregivers2,12,13. The neural mechanisms supporting these critical transitions are thought to be a shift from subcortical to cortical control1,6,8,14-16, with initial reflex- like predispositions (subserved by subcortical structures) declining as cortical control matures. This account appears well-fitted by our eye-tracking data11, and suggests a very specific hypothesis in autism: in infants with autism, reflex-like (subcortically-mediated) orientation to the eyes of others may initially be intact, while the emergence of experience-dependent (cortically-mediated) voluntary eye-looking subsequently fails. Despite the appeal of this proposed model, no studies have prospectively tracked the development of these neural systems and their relationship to unfolding behavior in typical development, a critical step before examining disruptions thereof in autism. In N=50 typical infants we will examine developmental changes in brain connectivity associated with 2 critical transitional behaviors, eye-looking and social-smiling, to identify: (1) brain networks differentialy associated with either decline in reflexive eye-looking or with the emergence of voluntary eye-looking, (2) brain networks differentially associated with either the decline of endogenous, reflexive smiling or with the emergence of socially-elicited smiling, and (3) brain networks common to social adaptive action. Behavioral and neuroimaging measures will be collected longitudinally at 7 and 3 time points, respectively, between birth and 6 months. Brain connectivity will be measured both structurally (as tract- specific diffusion parameters, including fractional anisotropy (FA) and mean diffusivity (MD), via diffusion tensor imaging (DTI) and tractography) and functionally (via measures of resting-state functional connectivity).

Project Summary The overarching goal of the present proposal is to understand how individual differences in the structure and function of Locus Coeruleus (LC) moderate perception and memory in an older adult population. There is substantial evidence that the LC circuit plays a central role in cognitive processes and neuronal loss in LC is known to occur in neurodegenerative disorders such as ADRD and PD. Integrity of LC neurons is hypothesized to mediate the preservation of cognitive abilities during normal aging as well. To date, however, there exists a dearth of research that either characterizes differential effects of LC integrity or details relationships between LC integrity and cognitive function in older adult humans. More generally, the link between LC activity and cognitive processes has not been well characterized in humans. Historical reasons for this is that the LC has been difficult to image due to its small size and thus most human research makes inferences about LC function by using pupil dilation as a surrogate measure. To overcome existing limitations in the field, we propose a series of detailed psychophysical and MRI-based studies in older adults aimed to characterize how LC structure and function moderates behavior and in turn how this is mediated by activity in intermediate brain regions known to be involved in perceptual and memory processes. We further propose computational approaches to characterize individual differences in how LC circuit integrity relates to different patterns of cognitive performance across tasks, and advanced neuroimaging methods to localize and image the LC, which have been pioneered by our group. Using MRI-based methods, we will examine LC integrity using high-resolution neuromelanin-sensitive structural imaging, tractography and functional connectivity. This approach will allow us to identify candidate biomarkers of LC circuit integrity. We will use a series of within-subject designs where we manipulate LC activity and examine whether relationships between LC and behavior and brain regions thought to mediate those behaviors are consistent or not between different perceptual modalities and memory tasks. Overall this study will provide an important and much needed understanding of how LC integrity underlies cognitive declines in older adults. By combining advanced neuroimaging, well-controlled behavioral assessment, and computational analysis, we expect to uncover previously inaccessible in vivo mechanisms of LC modulation and generate a unique dataset to address fundamental mechanistic questions of how the LC integrity moderates cognition, how this varies across older adults and the extent to which relationships between LC and cognition are generalized or individualized to particular domains. The resulting understanding of LC circuit can help explain how dysfunctional modulatory circuits may generate cognitive declines or be implicated in normal aging and age- related disorders such as Alzheimer's and Alzheimer's related disorders. This, in turn, has potential to support non-invasive methods for diagnosing pathologies associated with LC decline and developing new treatments.