Tony W. Wilson, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Soft neurological examinations in patients with psychotic illnesses have indicated salient sensorimotor abnormalities emerge early in life and are sustained through adulthood. The current proposal would investigate the neural basis of these sensorimotor aberrations in children with schizophrenia and matched controls. Using magnetoencephalography (MEG), the neuronal dynamics of sensorimotor processing will be probed during volitional finger movements and passive somatosensory stimulation. MEG analyses will utilize a beamforming approach that precisely images spatiotemporal activation patterns within a normalized space. In conjunction with the behavioral tasks, this imaging protocol will allow evaluation of interactive processes between motor and somatosensory cortices, as well as functional indices of each area in relative isolation. The results of this study could provide crucial data on the anomalous neural mechanisms underlying the sensorimotor abnormalities. Although these deficits are characteristic of schizophrenia patients at all ages, acquiring such knowledge in children will facilitate the identification of early neurophysiological markers of the illness, which could be especially important for earlier and more accurate diagnosis. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Combination antiretroviral therapy (cART) has dramatically shifted the nature of HIV-infection from a terminal illness to a chronic manageable condition, with a life expectancy close to that of the general population. However, infected patients remain at a significantly increased risk of developing HIV-associated neurocognitive disorders (HAND), with 35-70% of all patients (treated and untreated) exhibiting at least subtle impairments in neuropsychological function. This revised R01 proposal from an early-stage investigator (ESI) will examine the neurophysiological bases of HAND, identify markers of HAND progression, and determine how chronic HIV- infection modulates the normal effects of aging on cognitive performance and brain physiology. Over the past two years, my laboratory has evaluated the impact that cART treated HIV-infection has on neural activity and neuropsychological (NP) function through a series of imaging studies using magnetoencephalography (MEG). MEG is a noninvasive and direct measure of neuronal activity with millisecond temporal resolution and good spatial precision (3-5 mm). Using MEG, we have demonstrated neurophysiological abnormalities in the frontal eye fields, dorsolateral prefrontal cortex, and other association cortices, as well as deficits in the primary motor cortex. Most commonly, we have found hyper-activation in association cortices and hypo-activation in primary sensory and motor areas of patients relative to uninfected controls. We have also shown that activation metrics in specific brain areas correlate with scores on NP tests, and that the effects of aging on neuronal activity and cognitive function follow a distinct trajectory in HIV-infected patients compared with controls. Anchored by these extensive preliminary findings, we propose that MEG imaging is uniquely sensitive to the pathophysiology and progression of HAND, and to the additive effects that HIV-infection and aging have on neuronal function. To this end, we will examine 162 adults, 81 HIV-infected patients and 81 demographically-matched controls, divided equally into three age-specific groups (i.e., 22-38, 39-55, and over 55 years). All participants will undergo high- density MEG recording during a series of cognitive tasks, complete several MRI/DTI protocols, and perform a battery of NP assessments that adheres to the recommendations of the Frascati consensus [7]. To evaluate the progression of HAND, a subset of participants (infected and uninfected) will be followed longitudinally at 1.5-year intervals. The Specific Aims of this project are to: (1) Determine the neurophysiological bases of HAND by comparing HIV-infected patients who are impaired, according to the Frascati criteria, to those who are unimpaired; (2) Identify neuronal markers of HAND progression through a short-term longitudinal study of controls and impaired patients, who will undergo repeated MEG and NP testing sessions at 1.5 year intervals; (3) Determine how aging modulates NP function and neuronal activity in patients and controls, and identify the independent effect of HIV-infection on these parameters. We expect that the cognitive and neural deficits associated with HIV-infection will be significantly exacerbated by the aging process in critical brain networks.

Project Summary/Abstract This amended R03 proposal is for a NIDA-sponsored, AIDS-Science Track Award for Research Transition (A- START; PA-15-290). The primary goal of the A-START program is to support the entry of new and early career investigators into the area of drug abuse research in HIV/AIDS, particularly those whose current research program focuses on either drug abuse or HIV/AIDS, and who now wish to expand their program and study the intersection of these two areas. The PI of the current proposal is an early career investigator who received his first R01 award in August 2014 for a multimodal neuroimaging study examining how HIV-infection modulates age-related cognitive decline. Since then, he has received an administrative supplement to expand enrollment and examine sex differences in the R01 project, and been involved in other successful grants as a co- investigator. The PI is strongly committed to a career in neuroAIDS research, and through an A-START will expand his research program into the neurobiology and neuropsychology of drug abuse in HIV/AIDS, with a long-term focus on how substance abuse affects the incidence and severity of HIV-associated neurocognitive disorders. Such disorders are the most common neurological complication of HIV disease, with prevalence estimates ranging from 35-70% of all HIV-infected patients, and research targeting such comorbidities has been identified as a top priority by the Office of AIDS Research (see NOT-OD-15-137). The primary research goals of this project are to quantify the unique neuropsychological and neurobiological consequences of chronic marijuana abuse in HIV-infected patients. To this end, we will study demographically- matched groups of HIV-infected and uninfected heavy, light, and non-users of marijuana. All participants will undergo neuropsychological testing, high-resolution structural neuroimaging, and dynamic functional imaging with magnetoencephalography (MEG). MEG is an emerging method that directly quantifies neurophysiological activity and can produce functional maps with high spatial precision and millisecond temporal resolution. Data for the HIV-infected and uninfected light and non-user groups will be collected through the PI?s R01 project, which uses the same neuropsychological and imaging methods, but considers heavy use to be an exclusion criteria. Importantly, only four studies have examined the impact of marijuana abuse on cognitive function in HIV-infected patients, and these studies reported mixed results. Further, no study to date has evaluated brain structure or function in this area. Thus, the consequences of marijuana abuse in HIV-infected patients remain largely unknown, which is especially concerning as we enter an era of marijuana legalization. In summary, this A-START project will: (a) provide seminal neuroimaging and neuropsychological data on how HIV-associated neurocognitive disorders may be affected by chronic marijuana use, (b) contribute novel insight into whether the severity of neurological complications connects with the extent of marijuana consumption (heavy vs. light), and (c) serve as a springboard for the PI to begin drug abuse research in HIV/AIDS.

Project Summary/Abstract HIV-infected adults in the western world have a life expectancy near that of the general population, but are at a significantly elevated risk of developing cognitive impairments. Such impairments are the most common neurological complication of HIV disease, with prevalence estimates ranging from 35-70% of all HIV-infected individuals. Research targeting such comorbidities has been identified as a top priority by the Office of AIDS Research (NOT-OD-15-137). While the mechanisms underlying these deficits are not well understood, numerous human neuroimaging studies have examined the brain areas that may be involved, and overall these studies have been largely successful in identifying the critical hubs and networks. However, many questions remain regarding basic circuit dysfunction within these brain regions, and consequently there is a clear and common need to further investigate the neural dynamics and connectivity, as well as other key physiological parameters that may underlie the development and progression of HIV-related cognitive dysfunction. This proposal responds to RFA-MH-18-610, which requests proposals that ?advance knowledge of the etiology of mild to moderate forms of HIV-related cognitive dysfunction by clarifying the role played by altered neuronal circuits, receptors, and networks,? using ?novel neuro-electrophysiological and neuroimaging techniques.? The Multimodal Imaging of NeuroHIV Dynamics (MIND) Consortium responds to this call with an innovative, large- scale multimodal neuroimaging study that uses the latest breakthroughs in instrumentation and data analyses to identify the pathophysiology of neuroHIV in virally-suppressed adults. Specifically, the consortium will use advanced magnetoencephalographic (MEG) imaging to quantify the region- and circuit-level neural dynamics serving cognitive processing, 3-Tesla MRI and multimodal parcellation methods to map areal brain architecture, functional MRI (fMRI) for hemodynamics and intrinsic networks, and 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to quantify GABA levels in multi-voxel slabs of interest identified by the functional modalities. The investigative team includes a unique combination of experts in MEG, MRI/fMRI, MRSI, and cognitive psychology from the University of Nebraska and University of Pittsburgh Medical Centers (UNMC/UPMC). In addition, this consortium will harness existing resources such as the Multicenter AIDS Cohort Study (MACS) database and the National NeuroAIDS Tissue Consortium (NNTC) and, consistent with the RFA, will follow the Research Domain Criteria (RDoC) framework to define cognitive constructs. The consortium?s overarching hypothesis is that HIV-infected adults will exhibit aberrations in local inhibitory circuits, and that these deficits will alter gamma oscillations and thereby impair neuronal coding and interregional functional connectivity in the theta range. Such gamma deficits would provide robust explanatory power for the breadth of pathophysiological findings in the existent literature, and the MIND study is uniquely powered to investigate the underlying sources of these deficits, which are likely multifactorial (e.g., medical history, lifestyle factors, CNS viral penetration).

Project Summary/Abstract HIV-infected adults in the western world have a life expectancy near that of the general population, but are at a significantly elevated risk of developing cognitive deficits. Such impairments are the most common neurological complication of HIV disease, with prevalence estimates ranging from 35-70% of all HIV-infected individuals, and research targeting such comorbidities has been identified as a top priority by the Office of AIDS Research (NOT-OD-15-137). Substance use disorders (SUD) are also more prevalent in the HIV-infected population, yet their relative contribution to the increased rate of cognitive impairment in this group remains poorly understood. A key barrier to progress in this area has been the historic lack of diagnostic tests and biomarkers that can precisely assess the neurological complications of HIV-infection, which has all but precluded quantification of the additive impact of SUD comorbidity. This barrier is central to RFA-DA-18-023, which requests applications that ?foster biomarker and signature identification that could advance the clinical assessment of the degree of deterioration or damage, of functional reserve, and of resilience of host defense mechanisms, towards HIV- infection and comorbidity of HIV with SUDs.? Specifically, the RFA requests proposals that identify biomarkers derived from blood, plasma, noninvasive neuroimaging modalities, and/or other sources, with an emphasis on biomarkers that can be quantitated, with levels assessed for their ability to predict disease progression. The current project directly targets the scientific gaps identified in this RFA, Identification of Biomarkers of HIV Pathogenesis and Substance Abuse Comorbidity, using a multipronged approach that includes state-of-the-art neurophysiological, structural, and spectroscopic noninvasive imaging, cognitive assessment, and cellular and molecular analyses of blood/plasma in the context of cannabis use disorder (CUD). Specifically, the Signatures of Cannabis Abuse in NeuroHIV (SCAN) Consortium will utilize advanced magnetoencephalographic (MEG) imaging to quantify the neural dynamics serving cognitive processing, 3-Tesla MRI and multimodal parcellation methods to map brain architecture, functional MRI (fMRI) for hemodynamics and intrinsic networks, and 7-Tesla spectroscopic imaging to quantify local GABA levels across the brain. These data will be integrated with a comprehensive molecular screen that includes 35 plasma biomarkers covering the immune, inflammatory, coagulation, endothelial, and neurological systems, a 10-color flow cytometry panel delineating CD4 and CD8 T cells, B cells, NK cells, monocyte subsets, and activation markers, known clinical markers, and mitochondrial function in immune cells using the Seahorse Analyzer method. To enhance rigor, demographically-matched groups of uninfected controls with and without CUD will be enrolled, which will enable the interaction of HIV and CUD to be quantified. In sum, to truly meet the goals of this RFA, we will use a broad range of neuroimaging, molecular, and cellular functional assays to uncover biomarker signatures of HIV and CUD that will enable identification of early dysfunction, progression, and prognosis, enabling future preventative and treatment trials.

Project Summary/Abstract This proposal responds to RFA-MH-17-245, which requests applications focusing on the mechanisms and dose- response relationships of noninvasive neuromodulatory methods. To be considered responsive to this BRAIN Initiative related call, applicants must deliver noninvasive stimulation to a specific anatomical target(s) and/or circuit, and be able to precisely measure the effect of dose on neural activity within the target. In this project, we alter spontaneous cortical rhythms within visual attention circuitry using high-definition transcranial direct-current stimulation (tDCS), and quantify outcomes in terms of neural oscillations and behavioral performance utilizing a dynamic functional mapping approach based on magnetoencephalographic (MEG) imaging. Briefly, even in the absence of endogenous and exogenous inputs, neurons in the human cerebral cortex are known to exhibit spontaneous discharges and fluctuations in dendritic currents, as well as other electrical field activity. These neural phenomena locally summate and give rise to population-level rhythms often referred to as ?spontaneous activity,? which is ubiquitous across the human brain. While the pervasiveness of these rhythms is well known, their impact on the neural oscillations that serve cognition and underlie behavioral performance remains largely unknown. Herein, we propose and test a predictive model whereby the power of spontaneous activity adaptively regulates the dynamic range of a neural population, and that this governs the strength of oscillations within the population and thereby behavioral performance in real time. Our Aims are based upon extensive preliminary data emerging from two convergent research themes within our laboratory, and in this project we fully integrate these two areas to elucidate the basic tenets of circuit function during visual attention processing. Specifically, in Aim 1, we investigate a large group of young adults and use MEG to quantify how the power of pre-stimulus spontaneous activity, at distinct frequencies, governs the strength of oscillatory responses at the same frequency within a given neural population, and in-turn how this oscillatory amplitude dictates behavioral performance. In Aim 2, we systematically modulate local spontaneous activity within discrete frequency bands by applying high- definition tDCS to the visual cortex of the same young adults from Aim 1. Based on extensive preliminary data, this will enable us to both increase and decrease spontaneous power at targeted frequencies within these neural populations, and then quantify the effect of these manipulations on oscillatory responses to, and subsequent performance on, visual attention tasks. Finally, in Aim 3, we will enroll a large group of older adults who are known to exhibit naturally-elevated spontaneous activity, apply tDCS to modulate such activity, and then again measure the outcomes in terms of behavioral performance and oscillatory amplitude. Together, these methodologically-integrated experiments will provide pivotal insights into how tDCS quantitatively affects cortical physiology and, in turn, clarify the mechanisms by which human neural circuits incorporate pre-stimulus ?spontaneous? activity states with stimulus-related information within discrete networks.

Project Summary/Abstract The Research Domain Criteria (RDoC) project initiated a framework for developing research classifications based on functional dimensions emerging from translational research on genes, behaviors, circuits, and other cognitive-biological parameters. Almost a decade later, RDoC has grown into a matrix consisting of functional domains (e.g., cognitive systems), domain-specific constructs (e.g., attention, perception), and units of analysis for measuring each construct (e.g., physiology, behavior, genes, etc.). Numerous studies have contributed to defining each construct in terms of cognitive-biological parameters, and while these efforts have been broadly successful, the dimensional RDoC constructs themselves remain largely unvalidated. This lack of adequate validation is central to RFA-MH-19-242, which requests proposals that ?perform unbiased data-driven validation of existing constructs that may involve merging, subdividing, or hierarchically organizing them by integrating data between and within constructs.? Specifically, the RFA calls for studies that use ?multiple behavioral tasks and levels of analysis per construct,? ?multimodal data fusion ? to unbiasedly classify and compare constructs,? and ?data-driven definitions of constructs that involve structural and functional data on how brain states, networks, circuit dynamics, and hierarchies in the signals relate to outputs from task-based assays.? The RFA also encourages the use of ?accelerated longitudinal designs, with a particular emphasis on development ? and cutting-edge computational approaches to classify, predict, and explain developmental trajectories.? The Developmental Multimodal Imaging of Neurocognitive and (Epi)genomic Dynamics (Dev- MIND) Consortium responds to this call with an innovative, large-scale developmental multimodal neuroimaging study that will leverage previously-developed longitudinal pediatric cohorts and data fusion algorithms that this team established through the NSF-supported Dev-Cog project. Specifically, Dev-MIND will evaluate the unitarity and potential hierarchical structure of three constructs within the cognitive systems domain (i.e., attention, cognitive control, and working memory) using a battery of custom cognitive tasks, multimodal imaging, (epi)genomic analysis, an accelerated longitudinal design, and data-driven similarity metrics for construct validation testing. Our neuroimaging approach will include dynamic functional mapping based on magnetoencephalography (MEG), high-resolution volumetric MRI analyses based on multimodal parcellation, and functional MRI (fMRI) for whole-brain dynamic functional connectivity. These neuroimaging and behavioral performance metrics will also be combined with (epi)genetic data to identify covariance between genomic, cognitive, and neural activity patterns. Such data-driven approaches will enable classification and prediction of developmental trajectories per construct, and are central to the goals of computational psychiatry. In sum, this project brings together leading investigative teams, an array of state-of-the-art neuroimaging technology, and cutting-edge analytical methods to perform unbiased, data-driven validation of existing RDoC constructs.

Project Summary/Abstract: Research Project (A) Our long-term goal is to understand the impact of hormones on the neural mechanisms underpinning specific maladaptive processes associated with psychopathology, which will facilitate the development of improved treatment strategies. Estimates indicate that over 20% of American adolescents suffer from serious psychopathology, including stress, mood, anxiety, and behavioral disorders. Patients with these disorders show deficits in emotion regulation, part of the cognitive control construct within the Research Domain Criteria framework. Importantly, the prevalence rates of these psychiatric disorders increase during the transition from childhood to adolescence, coinciding with drastic pubertal changes in hormone levels. Furthermore, biological sex has been shown to substantially influence both hormone functioning and the prevalence of these disorders. Thus, our objective in this application is to identify the role of testosterone (T) and cortisol (C) reactivity in modulating neural activity associated with emotion regulation in male and female adolescents without and with psychopathology (i.e., emotion regulation issues). Consistent with the NIH?s mission to reduce the burden of mental disorders, the proposed work will yield a better understanding of the biological mechanisms underpinning emotion regulation, and thereby support the development of new and improved interventions for adolescents with psychopathology. The current proposal aims specifically to (i) clarify the extent to which T reactivity modulates emotion regulation and neural function in youth with psychopathology (i.e., emotion regulation issues) relative to typically-developing (TD) youth, and the degree by which pubertal status mediates this relationship in each group; (ii) determine the role of C reactivity in emotion regulation and neural function in youth with psychopathology and TD youth, and the degree to which pubertal status mediates these relationships and; (iii) identify the role of biological sex in modulating T and C reactivity in the context of emotion regulation in youth with psychopathology relative to TD youth. These aims will be accomplished by recruiting 238 adolescent participants (aged 9-15 years; half female; half community controls), including 119 adolescent patients with psychopathology (i.e., emotion regulation issues) from an academic medical center?s psychiatry clinic. Participants will complete an fMRI paradigm assessing emotion regulation following a social challenge paradigm designed to elicit a T response. Pilot data indicates that increased T response improves emotion regulation in healthy youth, but impairs it in youth with psychopathology. Further, the role of C in these disorders is unknown. It is anticipated that the proposed study will show the extent to which T and C reactivity each impact behavior and neural activity related to emotion regulation in youth with psychopathology, particularly across pubertal development. Additionally, sex differences in these relationships will be examined. As current intervention strategies for psychopathology do not consider hormonal mechanisms, these data will be important in the development of novel treatment modalities.

Abstract/Summary: Administrative (TEEAM) Core The Cognitive Neuroscience of Development and Aging (CONDA) Center will be a NIGMS-supported COBRE located in Omaha, NE, with a focus on human neuroscience and neuroimaging research across the lifespan. The Administrative Core will be essential to the development, support, and evaluation of all major components of this Center. Given these responsibilities, the Administrative Core will be known as the Training, Evaluation, Engagement, Administration, and Mentoring (TEEAM) Core. The Core will be directed by Dr. Tony Wilson of the University of Nebraska Medical Center, with the assistance of a Master?s-level Scientific Administrator. Upon establishment of the CONDA Center, the TEEAM Core will launch a series of new and integrated programs, each aimed at supporting one or more of its requisite areas. Specifically, the Training area will be served by a series of annual neuroimaging and neuromodulation workshops, as well as a postdoctoral fellow- ship program. The Evaluation area will be served by research development forums and will use other tools for assessing progress and milestone achievement in the junior COBRE PIs. The community Engagement area will support two outreach programs, NeuroWow and BrainFit, to engage youth and senior citizens, respectively, through organized events that help educate the public, promote STEM interest and careers in the Omaha area, and increase the public?s pride in regional science. The youth-oriented NeuroWow program has already been active for several years and will be expanded through additional support from the Center, while the BrainFit program will be the first of its kind in the region. The Administration area will oversee a Summer Scholars program that offers 10-week research internships in the Center to promising undergraduates, administrate a Pilot Projects program for faculty and a Mini-Grants program for postdoctoral fellows and graduate students that together will award about $180,000 annually, and invest financial and material resources into building a participant registry. The Administration area will also host the monthly CONDA Seminar Series, which will bring internationally-known cognitive neuroscientists to Omaha to present their latest findings and network with local scientists, potentially fostering new collaborations with Center members. Finally, the Mentoring area will use a network approach comprised of both academic and technical mentors to help ensure a successful transition of the junior COBRE PIs to independent investigators, guide postdoctoral fellows toward faculty positions, and assist junior and senior PIs who wish to enter new research areas relevant to the Center. Through these targeted programs and a strong network of established mentors and advisors, the TEAAM Core will support four junior COBRE research projects led by NIH-defined early-stage investigators (ESI), a state-of-the-art Neuroimaging Acquisition and Analysis Core Facility, and a collection of existing extramurally-funded research projects led by a team of senior investigators interested in human developmental and aging neuroscience.

Abstract/Summary: Neuroimaging Acquisition and Analysis Core The Neuroimaging Acquisition and Analysis Core will be the only core facility dedicated to human brain research in the state of Nebraska, and the only research core facility of the Cognitive Neuroscience of Development and Aging (CONDA) Center. This new Core Facility will provide neuroimaging infrastructure and analysis expertise to four institutions concentrated in a narrow stretch of downtown Omaha: the University of Nebraska Medical Center (UNMC), the Boys Town National Research Hospital, the University of Nebraska ? Omaha, and Creighton University. The Core will house a collection of state-of-the-art, research-dedicated neuroimaging and neurostimulation equipment, including a 306-sensor magnetoencephalography (MEG) system, a 3.0T Siemens Prisma magnet with high-performance gradients and a 64-channel head coil, new electrical and magnetic brain stimulation equipment, extensive high-performance computing resources, and other tools for advanced cognitive neuroscience research. The associated equipment and space has underwent significant renovations and upgrades during the past three years, and already serves a rich community of users comprised of members of multiple research programs led by established PIs with significant NIH, NSF, and/or foundation awards. The Core will also play a vital role in all four of the primary COBRE research projects, nurture the emergence of new research through the Pilot and Mini-Grant programs of the CONDA Center, and host instructional workshops and other training events. Thus, the Core?s community of users is expected to significantly increase throughout Phase I. The Core Facility will be directed by Dr. Tony Wilson (UNMC) who is an internationally- known expert with extensive experience in multimodal imaging, brain stimulation, and advanced data analytics. In summary, the combination of cognitive neuroscience, advanced neuroimaging, cognitive development, and brain and cognitive aging will create excellent opportunities for synergistic interactions within the new Core Facility, and these will spark new research ideas and programs, which will further grow the Core and the CONDA Center as a whole.

Project Summary/Abstract: Research Project (C) By 2060, adults 65 years of age and older are predicted to make up 24% of the U.S. population. Therefore, factors that impact older adults? cognitive and emotional health are of significant concern. Of particular importance are age-related declines in specific subtypes of empathy. These declines greatly impact public health because reduced empathy has been associated with numerous mental health conditions, including increased depression and loneliness. It is important to note that reduced empathy not only affects healthy older adults, but also appears to be selectively affected in specific age-related neurological disorders such as fronto- temporal dementia and Alzheimer?s disease. Therefore, characterizing the mechanisms underlying age-related declines in the subtypes of empathy could provide key information to develop targeted interventions that could have a major impact on aging-related diseases, as well as the many other patient populations affected by low empathy (e.g., autism, schizophrenia, traumatic brain injury). Current research suggests that there are two subtypes of empathy (i.e., cognitive and emotional) and that healthy older adults show significant declines in the cognitive subtype of empathy (i.e., understanding others? thoughts and feelings), with preserved or enhanced function in the emotional subtype (i.e., feeling compassion for others). These declines in cognitive empathy have been linked to neural changes in regions associated with thinking about others? mental states, such as the dorsomedial prefrontal cortex. Moreover, there is evidence suggesting that declines in cognitive empathy may be at least partially attributable to age-related deficits in other cognitive functions, such as executive function and memory. However, little is known on the neural bases of preserved emotional empathy in older adults, and the trajectory of neural and behavioral function underlying each empathy subtype has never been examined across the adult lifespan. Furthermore, while previous studies have focused on relationships with chronological age, they have not measured the link to biological age, which has been shown to be a more accurate marker of the physiological impacts of lifespan stressors and is predictive of disease risk and all-cause mortality. To address these gaps in knowledge, this proposal will investigate the trajectory of age-related changes in the cognitive and emotional subtypes of empathy through behavioral and functional neuroimaging methods. Participants will include 116 healthy adults ranging in age from 25-75 years of age. Gold standard cognitive and emotional empathy tasks will be used to probe age- related behavioral changes, and functional MRI will be used to assess neural changes, in both intrinsic networks and task-based activation during empathy tasks. Aging will be assessed using both chronological and biological aging (based on DNA methylation) metrics to provide a more precise quantification of the aging process. The results of this proposal will lay the groundwork for the development of interventions designed to target specific subtypes of empathy, with widespread implications for the clinical populations experiencing reduced empathy.

Project Summary/Abstract The Omaha MEG site is one of the most productive, internationally-known MEG groups in the world. In 2018 alone, they published more than 20 peer-reviewed publications in top journals (e.g., Brain, Neurology), obtained numerous major NIH awards, and made high impact discoveries spanning multiple areas of human neuroscience. MEG, or magnetoencephalography, is an advanced method for noninvasively imaging population-level neurophysiological activity with high temporal (< 1ms) and spatial precision (2-3 mm). Application of the method has grown substantially over the past decade due to technical advancements and the growing interest in neural oscillations, dynamic connectivity, and other metrics where spatiotemporal precision is extremely important. The Omaha MEG group has had a major role in this growth and continues to lead the way in many areas of MEG research, often exceeding all other MEG sites on major measures of scientific productivity and impact. However, this group is now at a crossroads where their future growth, and even existence, is threatened by the helium shortage and the planned obsolesce of their current MEG instrument. Briefly, this instrument consumes over 100 L of liquid helium per week, which is not only very expensive but also increasingly difficult to obtain in the current era of helium shortages. The device could be retrofitted with a 70% efficient helium recycler, but that would be expensive and only a partial, temporary solution. Beyond this, their current device is almost 11 years old and the vendor will cease making replacement parts for their model at the end of 2019. Thus, even with helium, the device is nearing end of life. Given these concerns, we are proposing to replace our existing MEG system with a state-of-the-art Triux Neo MEG system from MEGIN (formerly Elekta). This new system is equipped with: (1) an almost 100% efficient helium recycling system, (2) advanced ARMOR sensors and electronics which significantly expand the system?s dynamic range and have lower intrinsic noise levels, (3) improved spatial precision, (4) a two-layer passively and actively shielded room with external environmental sensors, and (5) a new ergonomic design and fine positioning system to enhance patient comfort and ensure the most optimal head position relative to the array in each participant. Thus, this new system is a significant, major step forward for the Omaha MEG group and for the field as a whole, as the first Triux Neo installation was recently completed in the United States. With this device, the Omaha MEG group will continue to grow and attract the best new faculty and junior scientists, and will remain at the forefront of discovery in several major topic areas that are described in the proposal and of clear interest to the NIH and the translational neuroscience community.

Abstract: Imaging Core The Imaging Core of the Chronic HIV Infection, Aging and NeuroAIDS (CHAIN) Center consists of two laboratories, the Preclinical Imaging Laboratory (M. Boska, Co-PI) and the Human Structural and Functional Neuroimaging Laboratory (T. Wilson, Co-PI). The primary goals of the Core are to support CHAIN PIs and other neuroAIDS investigators in the identification and quantification of HIV-related alterations in brain function, structure, and metabolism, and to aid in understanding how emerging therapeutics modulate brain function to ameliorate and/or reverse these HIV-related alterations. Discovery of neural biomarkers of HIV-associated neurocognitive disorders (HAND) and the basic mechanisms of HIV-related brain injury remains a high priority, with 35-70% of all HIV-infected patients developing HAND in the post cART era. Surprisingly, despite this persistently high prevalence, there are currently no diagnostic tests or any specific biomarkers that can precisely pinpoint HAND, be used to monitor disease progression, or as an assay of an emerging treatment?s beneficial effects. The CHAIN Imaging Core has been designed for biomarker discovery and optimization, as the same imaging assessments can be performed in parallel in animal models and human trials. Such a parallel approach allows bidirectional feedback between animal and human studies, and will enhance abilities to diagnosis, monitor, and predict HAND in humans, while providing targets for detailed histological and biochemical studies of the underlying mechanisms. Alterations will be assessed with regard to age, viral status, sex, drug treatment, and effects of drugs of abuse. In short, this Core will use animal models of HIV-infection to provide noninvasive imaging indicators of altered neuronal function and neurotoxicity, and investigate the biochemical mechanisms of these functional abnormalities in collaboration with the Omics Core. Potential biomarkers of altered function can then be tested in humans in the Imaging Core using advanced structural and functional imaging in collaboration with the Developmental Core. Conversely, as functional deficits are detected in human studies, regions identified as demonstrating abnormal neuronal function can be targeted for more thorough investigation in animal studies to (1) replicate the findings using similar imaging methodologies in a better controlled model (e.g., without lifestyle issues) and (2) investigate the cellular and biochemical source(s) of these functional abnormalities in collaboration with the Omics Core and the Cell, Tissue, and Animal Core. These studies will provide new diagnostic capabilities, uncover the biochemical and functional deficits associated with HAND, and allow monitoring of the effects of new therapies on brain biochemistry and function in animals and humans.

Abstract/Summary: Overall Component This application for a Center of Biomedical Research Excellence (COBRE) would initiate a formal Center to lead, support, and expand neuroimaging and clinical cognitive neuroscience research in Nebraska, with an emphasis on lifespan development. It is an opportune moment for human neuroscience research in the Omaha community, regionally, and across the world, with many new research tools and government initiatives intended to illuminate the next frontier of biomedicine. The proposed Cognitive Neuroscience of Development and Aging (CONDA) Center will provide critical resources and support to faculty from four institutions: the University of Nebraska Medical Center (UNMC), the Boys Town National Research Hospital, the University of Nebraska ? Omaha, and Creighton University. The Administrative Core of the CONDA Center will be housed at UNMC, which is less than two miles from each of the other institutions, and will be comprised of Training, Evaluation, Engagement, Administration, and Mentoring areas (i.e., the TEEAM Core). The new CONDA Center will also include a state- of-the-art Neuroimaging Acquisition and Analysis Core, as well as extensive support for four primary COBRE research projects led by a promising group of NIH-defined early-stage investigators. Upon initiation of the Center, the TEEAM Core would immediately implement a series of new programs that are designed to develop human cognitive neuroscience on the CONDA Campus and across the region. The TEEAM Core would also rapidly implement a comprehensive research support structure that includes the Neuroimaging Core facility, training opportunities, pilot projects and mini-grants programs, a new seminar series, postdoctoral fellowships, intern- ships for growing temporary and long-term laboratory staffing, and a participant registry to enhance recruitment. In parallel, the TEEAM Core would promote the successful launch of the primary COBRE research projects and, through a mentoring network approach, implement a career development and evaluation support system to monitor progress and ensure Junior PIs and their mentoring teams reach critical milestones. As per the new research core, the Neuroimaging Acquisition and Analysis Core facility would be the only core dedicated to human brain research in the state of Nebraska, and would provide regional scientists with state-of-the-art tools for neuroimaging and neuromodulation, including research-dedicated MRI and MEG systems. The new Center would also receive exceptional institutional support, including financial support for CONDA programs, major equipment expenses, and Core staffing. The overall CONDA team includes an established group of PIs in neuro- imaging, brain dynamics, aging, and brain and cognitive development, as well as a strong cohort of emerging junior investigators using innovative cognitive and affective neuroscience methods to address major questions in human neuroscience across the lifespan. These junior scientists were all hired in the past three years, and this new wealth of concentrated local expertise has primed us for a trajectory of accelerated development of neuro- science and neuroimaging toward national prominence, an aim for which the new CONDA Center will be integral.