Paul J. Laurienti - US grants

DESCRIPTION (provided by applicant): The research project is designed to study cross-modal sensory processing in aging as it has been shown that all sensory systems exhibit diminished function with age and recent studies have suggested that the integration of information from multiple sensory modalities (cross-modal processing) is affected by normal aging, interestingly, many of the disabilities associated with aging that impact the quantity of life, such as increased fates, communication disturbances, and memory impairment may be associated with alterations of cross-modal processing. The Specific Aims for this project are purposely designed to identify behavioral and neural changes in cross-modal processing that occur with age. Neural responses will be measured using functional magnetic resonance imaging (fMRI). Subjects will be studied during passive cross-modal stimulation, during a cross-modal matching task, and during a cross-modal integration task. Neural activation patterns and behavioral data will be analyzed to identify dysfunctional brain areas that correlate with diminished cross-modal processes. Because cross-modal processes are intimately involved in nearly all aspects of sensory processing and play critical roles in language processing, spatial orientation, and memory, a better understanding of changes that occur with age may help shed light on many of the problems experienced by aged individuals. The candidate has completed clinical (M.D,) and basic science (Ph.D.) training and has the desire to pursue a career in clinical research. The training program will include didactic instruction in statistics and statistical software programming. Through the guidance of his co-mentors, the candidate will master the skills necessary to perform scientific studies in patient populations. His goal is to combine the information acquired throughout his education to enable him to study diseases of the human brain as an independent investigator. The Wake Forest University School of Medicine is an environment that will allow the applicant to excel in the clinical neurosciences. The Department of Radiology has an active fMRl research program and is dedicated to expanding the neuroimaging research group. The J. Paul Sticht Center on Aging and Rehabilitation serves as the hub of research and teaching activities as well as a key location in the clinical treatment of elderly patients.

DESCRIPTION (provided by applicant): Caffeine is the most widely used neurostimulant in the world, and it has been shown that 79% of the population in the United States drinks coffee at least occasionally. This high incidence of use is of considerable significance because caffeine can modulate multiple physiological imaging measures. The effects of caffeine are due to the nonselective antagonism of adenosine receptors, acting not only as a vasoconstrictor but also as a neurostimulant. It has been proposed that the caffeine-induced decrease in resting cerebral perfusion will allow for a greater difference between resting and active states in a BOLD study, thus increasing the magnitude of the signal. However, it is well known that chronic caffeine use causes an upregulation of adenosine receptors. Thus, the administration of caffeine as a BOLD signal enhancer is likely complicated by neural and vascular responses and by differences in receptor numbers dependent on the individual's dietary caffeine consumption. In fact, resting perfusion decreases have been found to produce variable effects including both increases, decreases, or no consistent change in the BOLD signal amplitude. The conflicting results are likely due the fact that previous studies have either not controlled for caffeine consumption or have been limited to withdrawal states. The broad, long-term objective of this project is to gain a more thorough understanding of the effects of caffeine and adenosine on brain activity and blood flow, and how such effects modulate physiological brain imaging measures. Our primary hypothesis is that caffeine modulates neural activity-induced changes in regional cerebral blood flow through 2 mechanisms: 1.) caffeine indirectly increases blood flow by blocking neural receptors and increasing neural activity and 2.) caffeine directly decreases blood flow by producing vasoconstriction through the blockade of vascular receptors.

1,3,7-Trimethylxanthine; 1H-Purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl-; Adenosine; Affect; Blood Vessels; Blood flow; Brain; Brain imaging; CRISP; Caffeine; Cell Communication and Signaling; Cell Signaling; Cerebrovascular Circulation; Chronic; Computer Retrieval of Information on Scientific Projects Database; Consumption; Dose; Encephalon; Encephalons; Enhancers; Food and Beverages; Functional Magnetic Resonance Imaging; Funding; Grant; Institution; Intracellular Communication and Signaling; Investigators; Knowledge; Literature; MRI, Functional; Magnetic Resonance; Magnetic Resonance Imaging, Functional; Measures; NIH; NRVS-SYS; National Institutes of Health; National Institutes of Health (U.S.); Nervous; Nervous System; Nervous System, Brain; Nervous system structure; Neurologic Body System; Neurologic Organ System; Numbers; P1 Purinoceptors; Personal Satisfaction; Publishing; Purinergic P1 Receptors; Receptors, Adenosine; Receptors, Purinergic P1; Research; Research Personnel; Research Resources; Researchers; Resources; Rest; Signal Transduction; Signal Transduction Systems; Signaling; Source; System; System, LOINC Axis 4; United States National Institutes of Health; Vasoactive Agonists; Vasoconstrictor Agents; Vasoconstrictor Drugs; Vasoconstrictors; Vasopressor Agents; Withdrawal; biological signal transduction; blood oxygen level dependent; brain cell; brain visualization; cerebral blood flow; cerebral circulation; cerebrocirculation; fMRI; insight; interest; neural; relating to nervous system; response; vascular; vasopressor; well-being

[unreadable] DESCRIPTION (provided by applicant): It has been shown that as humans age all sensory systems exhibit diminished function. Interestingly, many of the disabilities associated with aging that may impact the quality of life, such as increased falls, communication disturbances, and memory impairment, may be impacted by changes in the integration of information from multiple sensory modalities. In fact, distractions from unattended or background stimuli in across sensory modalities are consistently increased in aged individuals. The enhanced response to background stimulation is thought to be related to changes in sensory attention that occur with age. Although more susceptible to distractions within or across sensory modalities, elderly subjects actually show greater behavioral performance enhancements when multisensory stimuli carry redundant information. Thus, many age-related sensory deficits could be ameliorated if elderly subjects were able to limit distractions associated with irrelevant sensory cues but retain the benefits associated with redundant multisensory cues. An intervention that reduces elderly subjects' susceptibility to distractions within and across sensory modalities may improve multisensory integration and could have a great impact on quality of life by improving processes such as communication and memory in addition to limiting susceptibility to falls. The studies proposed here will fill this knowledge gap by evaluating multisensory processing in elderly subjects before and after participation in an attention training program. Our primary hypothesis is that attention training lessens distractions associated with incongruent sensory stimuli while retaining behavioral improvements associated with congruent multisensory stimuli. A significant advantage of utilizing behavioral interventions over pharmacologic interventions is that the risk for adverse side-effects is very low. Thus, studies directed at evaluating the clinical efficacy of multisensory training programs could have considerable impact on health care and the quality of life in the elderly. [unreadable] [unreadable] [unreadable]

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Adults over 65 years of age have become the most rapidly growing sector of the United States population. It is of considerable concern that all sensory systems exhibit diminished function with age. Many of the disabilities associated with aging that may impact the quality of life may be impacted by changes in the integration of information from multiple sensory modalities. Distractions from unattended or background stimuli in multisensory stimulation paradigms are consistently increased in aged individuals, and the corresponding neural responses to such stimuli are also abnormally increased. The behavioral disruptions caused by task-irrelevant stimuli are accompanied by alterations in patterns of brain activity in older adults during tasks that require the suppression of interfering or conflicting information. In addition, while older adults maintain vigilance and sustained attention abilities equivalent to those of young subjects, their performance on selective or divided attention tasks deteriorates significantly. The study proposed here will determine the extent and magnitude of functional changes in brain activity in older adults who participate in an attention training program.

1,3,7-Trimethylxanthine; 1H-Purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl-; Agreement; Behavior; CRISP; Caffeine; Cell Communication and Signaling; Cell Signaling; Computer Retrieval of Information on Scientific Projects Database; Funding; Goals; Grant; Image; Institution; Intracellular Communication and Signaling; Investigators; Moods; NIH; National Institutes of Health; National Institutes of Health (U.S.); Research; Research Personnel; Research Resources; Researchers; Resources; Signal Transduction; Signal Transduction Systems; Signaling; Source; United States National Institutes of Health; Withdrawal; biological signal transduction; imaging

DESCRIPTION (provided by applicant): This application is for the renewal of a Short Term Medical student Training Grant first funded in 1980. These trainees will be medical students at the Wake Forest University School of Medicine. Funds are requested for support of 16 trainees for a 12 weeks research training period each. Trainees are selected on a competitive basis from research applications developed in conjunction with selected faculty members. Thirty to 35 applications are typically received. Selection is made by a faculty committee on the basis of the strength of the mentor to provide the student with a positive role model for research. Mentors are selected from the following 10 research areas encompassing the strongest research programs at the medical school. Metabolic Diseases, Cancer Biology, Public Health Research, Molecular and Cellular Biology, Kidney and Urology, Neurobiology and Addiction, Obesity and Nutrition, Women's Health and Minority Health, Immunology/Infectious Diseases/AIDS/Hematology, and Cardiovascular Disease. The primary training facility will be the research laboratories of the academic departments of the Wake Forest university school of Medicine. Clinical research activities will be carried out largely in the medical school's primary teaching hospital, the North Carolina Baptist Hospital. Students present their research in the fall of each year. The goal of this training program is to increase the number of medical students choosing research careers.

Farmworkers are frequently exposed to a wide variety of pesticides, including organophosphate, carbamate, and pyrethroid insecticides, all of which are neurotoxins. The doses of pesticides to which farmworkers are generally exposed, while frequent, are small. Therefore, the full effect of these neurotoxic pesticides may go undetected for years until manifest as a diagnosis of neurodegenerative disease. Research is needed to delineate the immediate, sub-clinical neurological signs of pesticide exposure among farmworkers. CPBR allows communities and universities to conduct research collaboratively and to address policy and regulatory changes. This project is based on established collaborations between Wake Forest University School of Medicine, North Carolina Farmworkers Project, El Buen Pastor Latino Community Services, and Toxic Free NC. This CBPR project will accomplish 5 specific aims: (1) delineate differences in pesticide exposure between Latino farmworkers who are exposed to agricultural pesticides and Latino manual workers who are not exposed to agricultural pesticides; (2) determine associations between pesticide exposure and neurologic function; (3) delineate the effects of pesticide exposure on changes in neurologic function among pesticide exposed Latino farmworkers and non-exposed Latino manual workers; (4) characterize the DNA methylation and gene expression patterns in pesticide exposed Latino farmworkers and non-exposed Latino manual workers, and determine if changes in neurologic function are associated with DNA methylation and gene expression patterns, and (5) address pesticide safety and health policy and regulatory changes through collaboration with members of the farmworker community, farmworker health and immigrant health advocacy groups, and policy makers and regulators. This project is significant and innovative. It includes a sufficiently large sample size, a long follow-up time, and appropriate neurological domains to evaluate the weight of evidence for neurological effects from pesticide exposure. It examines dose-response relationships for a set of biomarkers of pesticide exposure in an attempt to establish quantitative estimates of neurological outcomes. It combines multiple methods, including neurobehavioral, neurophysiological, and genomics. It provides a unique opportunity to study several clinically salient and important public health outcomes that are potentially responsive to interventions. It examines genetic factors involving metabolism of pesticides and genome-wide DNA methylation with etiological importance in the expression of neurological dysfunctions. This genomics-based approach is likely to identify associations with, and potentially the underlying mechanisms of, pesticide exposure and neurological function. This project is innovative in its attention to policy. It will follow a large cohort of adult farmworkers with an appropriate comparison group to document pesticide exposure and outcomes over multiple years. We have included policy change as an integral component and we will integrate policy development throughout the project.

Project Summary/Abstract Declining mobility function is a common age-related phenomenon that is associated with reduced quality of life and high societal costs. Recently, the brain's critical role in mobility function has been recognized using imaging approaches assessing white matter characteristics. A new paradigm considering the brain as a complex network uses MRI to directly characterize the brain as a functional network. Brain Networks and Mobility Function: B-NET brings together national leaders in brain network science, neurology and mobility assessment to apply this innovative network paradigm to elucidate the aging brain's role in declining mobility. We propose that functional connectivity within and between the sensorimotor cortex -- community structure (SMC-CS) -- predicts declining mobility; and that SMC-CS will be associated with mobility independent of known relationships between white matter integrity and mobility function. B-Net will establish a cohort of 240 community-dwelling older adults (age range 70-85) and measure mobility function at baseline, 6, 18 and 30 months using the extended short physical performance battery (eSPPB). The MRI will be repeated at 30 months. B-Net's specific aims are to: Specific Aim 1. Determine the baseline association between SMC-CS and eSPPB score. We hypothesize that SMC-CS will be associated with eSPPB performance independent of known correlates of mobility function and white matter integrity (i.e. fractional anisotropy and white matter lesions). Specific Aim 2. Determine whether baseline SMC-CS predicts mobility decline. We hypothesize that poorer baseline SMC-CS will be predict declining eSPPB scores after accounting for known correlates of mobility impairment including white matter integrity, cardiovascular fitness, and muscle strength. Specific Aim 3. Repeat brain MRI imaging to determine the longitudinal association between changes in SMC-CS and changes in eSPPB score. We hypothesize that longitudinal declines in SMC-CS will be significantly associated with declining eSPPB performance independent of known correlates of lower extremity function decline and white matter integrity. B-NET tests a novel emerging paradigm regarding the CNS's role in age-related functional decline to support the development of innovative strategies to sustain mobility function in older adults, a critical public health need.

Concern is mounting that commonly used pesticides are detrimental to children. Children are rapidly undergoing cognitive, sensory, and motor development, and disruption of normal maturation can have life-long consequences. The extant literature strongly indicates that prenatal exposure to pesticides leads to abnormal neurobehavioral development. A recent brain imaging study further showed that prenatal pesticide exposure is associated with disrupted anatomical brain development. However, results concerning the consequences of postnatal pesticide exposure are much less conclusive. Some studies have reported neurobehavioral deficits following postnatal pesticide exposure, but just as many studies have reported no negative consequences. Currently there are no studies that assess the effects of postnatal pesticide exposure on brain development using anatomical or functional brain imaging. More conclusive research on the effects of postnatal exposure on neurodevelopment requires a highly exposed population, a longitudinal design, and careful quantification of exposure and outcomes. We propose a two-group, prospective, longitudinal study of Latino children 7 years of age with quarterly measurement of cumulative pesticide exposure using passive dosimetry wristbands as well as documentation of prenatal and early life exposure through life history techniques. Children from Latino seasonal farmworker families will be compared with children from Latino families not participating in farm work and not living in an agricultural environment. Children in Latino farmworker families are at particularly high risk of exposure. Not only are pesticides frequently used in their low quality housing, but they are also exposed to agricultural pesticides used in nearby fields brought home by parental/sibling farmworkers on clothing. Children will be followed for 2 years with measurement of neurobehavioral function at baseline, 1 year, and 2 years. Neuroimaging will be performed in a subset of participants with structural and functional brain organization assessed at baseline and two years later. Specific aims for this project are: Aim 1: Compare 2-year longitudinal and prenatal/early life pesticide exposure between children of Latino seasonal farmworkers and children of Latino parents who are not farmworkers. Aim 2: Compare 2-year longitudinal neurobehavioral and emotional and behavioral functioning among children of Latino seasonal farmworkers relative to children of Latino parents who are not farmworkers. Aim 3: Compare 2-year longitudinal anatomical and functional brain development between children of Latino seasonal farmworkers and children of Latino parents who are not farmworkers. Our nearly two decades of environmental justice (EJ) and community-based participatory research (CBPR) on pesticide exposure with farmworkers and their families provides an auspicious context to engage this vulnerable population in a study of both scientific and environmental justice importance.

PROJECT SUMMARY The scientific premise of the Wake Forest Translational Alcohol Research Center (WF-TARC) is that the neurobiological substrates that contribute to alcohol use disorder (AUD) vulnerability and resilience are not fully understood. Despite the fact that alcohol misuse contributes to 88,000 deaths in America each year, the effectiveness of currently available interventions is less than desirable and is demonstrated by relapse occurring in up to 70% of treated patients. It is clear that we must better understand the neurobiology of AUD vulnerability so that patients can be identified early in the disease process and appropriate novel treatments can be developed. There is a growingly accepted three-stage model of addiction that is based on a recurring cycle of binge/intoxication, followed by withdrawal/negative affect, and ultimately preoccupation/anticipation of further use (craving). This project will focus on craving as a potential marker for AUD vulnerability as it is the primary predictor of AUD relapse. The first aim is designed to characterize the behavioral phenotypes and brain network properties associated with high craving in moderate-high alcohol drinkers (females 1-3 drinks/day, males 2-4 drinks/day). Participants must drink most days of the week but cannot have any history of, or currently meet criteria for, AUD. Ecological momentary assessment (EMA) methods utilizing iPhone technology will be used to assess craving during real time and in the participant's natural environment during normal drinking days, as well as during abstinence. Functional neuroimaging and brain network analyses will be used to examine associations between craving and brain connectivity. It is hypothesized that 1) individuals with high Alcohol Craving Experience (ACE) scores will have higher measures of EMA craving, and 2) the high ACE population will have high levels of connectivity between medial prefrontal cortex (mPFC) and posterior default-mode network (DMN) and low levels of efficiency between the mPFC and the ventral striatum and amygdala. Aims 2 and 3 will evaluate the effects of randomization to mindfulness meditation intervention versus a sham mindfulness intervention on the behavioral and brain characteristics associated with high craving in moderate-high alcohol drinkers. This will be the first placebo-controlled mindfulness meditation study to examine the behavioral and neural mechanisms supporting alcohol craving. It is hypothesized that mindfulness meditation will not only significantly reduce EMA measures of craving, but will decrease connectivity between the mPFC and posterior DMN and increase connectivity from the mPFC to the ventral striatum and amygdala. This project has the potential to guide the development of future clinical trials to better target clinical outcomes by understanding corresponding mechanisms supporting meditation-related reductions in alcohol craving. The identification of behavioral markers underlying craving as an indicator of vulnerability could lead to real-world interventions to prevent AUD.

The primary objective of this administrative supplement proposal is to transform the way dynamic functional brain network data is visualized, interpreted, and shared. There is a growing literature demonstrating the power of brain network analyses with more recent studies using dynamic brain network analyses to assess brain network changes over time. To generate functional brain networks, functional magnetic resonance (fMRI) data are processed to identify brain regions that are functionally connected. Dynamic brain network analyses yield ~ 200 brain networks for each study participant. These analyses result in extremely large datasets that are difficult to manage, visualize, and combine across studies. We propose to develop the methodology necessary to map dynamic brain network data into a standard 2-dimensional (2D) space to generate dynamic functional trajectories. An algorithm to map dynamic brain networks to this standard pace will be shared across brain imaging research studies. Data can then be viewed and interpreted in a consistent manner across studies allowing for direct comparison (including quantitative assessments) of results. This supplement is associated with the parent project ?Preventing Agricultural Chemical Exposure 5 (PACE5)? that is examining the effects of pesticide exposure on children of Latino farmworkers. The parent project will be collecting functional brain imaging, cognitive, and pesticide exposure data on 8-year old children at baseline and will follow the children for 2 years. Dynamic functional brain networks will be used to identify association with pesticide exposure and neurocognitive development. Ultimately this supplement will enhance data sharing across dynamic functional brain network studies and will enable us to combine data from the parent study of brain development in Latino children with data from existing databases and from ongoing or future studies examining the effects of environment exposure on brain development. The specific aims of this supplement are: Aim 1: Develop an algorithm that will allow for embedding high-dimensional dynamic brain networks in 2- Aim 2: Evaluate and demonstrate the utility of dynamic trajectory comparisons across studies by combing data from our prior PACE study and the Human Connectome Project (HPC). To enable the scientific community to use these new methods, the algorithms for generating dynamic trajectories in standard space will be made openly available. The software and documentation will be deposited in NITRC (https://www.nitrc.org/). Dynamic trajectories from our study will be made available for integration with other research projects. The new methodology will increase the overall value of our study by allowing us to readily share our data with other investigators and integrate data from other studies into our analysis and interpretation.

PROJECT SUMMARY/ABSTRACT Current treatments for Alzheimer's disease are minimally effective in slowing the progression because they can only be prescribed once symptoms of the disease are reported. By this time, irreversible neuron death and brain atrophy have occurred. Finding new, earlier biomarkers of Alzheimer's disease is imperative to developing new treatments that can target early prevention of neuropathological changes. Naturalistic tasks, including complex, everyday tasks and performing a cognitive task while walking (i.e., dual-tasking), require coordination of executive function, working memory, and visuomotor coordination, which are the cognitive functions that are typically impacted early on in Alzheimer's disease. Subtle declines in cognitive function may impact cognitive processing, visuospatial attention, and motor function, leading to impaired ability to perform these naturalistic tasks well before most patients report symptoms and thus may provide new, earlier biomarkers of high risk of developing Alzheimer's disease. Therefore, the goals of this project are to determine if measures of visuospatial attention and gait smoothness during performance of complex, everyday tasks involving walking can differentiate between older adults at high risk of developing Alzheimer's disease (pathological levels of beta amyloid accumulation), low-risk older adults, and young adults (Aim 1), and identify if dual-task costs on gait, visuospatial attention, and cognition can differentiate between high-risk older adults, low-risk older adults, and young adults (Aim 2). Thirty high-risk older adults (?70 to ?85 years), 30 low-risk older adults ((?70 to ?85 years), and 30 young adults will be assessed in 5 conditions: simulated grocery shopping task, walking on uneven ground task, cognitive single-task (performing an inhibition-executive function and a working memory task while seated), gait single-task (walking at fastest comfortable speed and at fastest comfortable speed while stepping over obstacles, without any simultaneous cognitive task), and dual-task walking (walking while performing cognitive tasks). This project will employ the concurrent recording of gait, eye movements, and cognitive performance to identify how gait smoothness, visuospatial attention, and dual-task costs on gait, visuospatial attention, and cognition can differentiate those at high- versus low-risk of developing Alzheimer's disease while performing naturalistic tasks. The proposed project is a supplement to B-NET (R01AG052419), a longitudinal study examining beta amyloid accumulation, neurocognitive function, and mobility functioning in older adults. Adding the proposed assessments to the data already collected in the parent study will provide an innovative examination of if a fine-grained analysis of cognitive processing, visuospatial attention, and smoothness of gait during naturalistic everyday tasks can serve as an early biomarker of risk of developing Alzheimer's disease.