Federal Grants

1. Stress Regulation, Working Memory, and Cognitive Disorganization In Adolescence, NIH National Institute of Mental Health (NIMH), Principal Investigator, 7/20/2015 – 5/31/2020.
   
   Abstract: Adolescence is a peak time for the emergence of the core symptoms of psychopathology. Cognitive disorganization (CD)
   is a key symptom dimension of psychosis that emerges most commonly in adolescence, predicts the onset and severity of
   psychotic disorders, and transcends DSM diagnostic categories. Although little is known about the biological
   correlates of CD, adolescents experiencing disorganization have significant deficits in working memory capacity
   (WMC) and arousal/stress regulation (ASR). These two behavioral constructs show dramatic maturational changes
   during adolescence, which are necessary for the transition to higher-level cognition, affect regulation and
   psychosocial adaptation. Despite the strong epidemiologic evidence for the role of stress in the etiology of
   psychosis, and the centrality of working memory impairments in psychosis, little is known about their contribution
   to CD in adolescence. Examining the neural and physiological systems associated with working memory and stress
   regulation in adolescence, and their contribution to CD severity, offers a critical step in elucidating the
   pathophysiological mechanisms that contribute to the onset of psychosis. This approach is consistent with the
   RDoC framework, which encourages using converging measurements to study the underlying neurobiology of domains
   (Cognitive System and Arousal Regulation in this proposal), and constructs (working memory capacity and stress
   regulation) that represent fundamental behaviors expressed by individuals with clinical risk symptoms for psychosis.
   We will use a multimodal approach integrating functional neuroimaging, electrophysiological, and behavioral measures to
   ascertain converging measures of working memory and arousal/stress regulation constructs across neural, physiological,
   and behavioral units, and to characterize the contributions of atypical ASR and impaired WMC in the severity of CD symptoms.
   In Aim 1, we will evaluate the contributions of working memory impairments and atypical arousal/stress regulation in 180
   adolescents (ages 9-16) to the severity of CD symptom. In AIM 2 we will model the relationship between WM and ASR constructs
   and their impact on CD severity. In AIM 3, we will examine the longitudinal trajectory of CD symptom severity, behavioral and
   electrophysiological measures of WM and ASR, and their associations with baseline neural, behavioral, and physiological
   measures acquired in AIMs 1 and 2. For each aim, we will explore the modulatory role of sex differences and pubertal
   maturation on stress-regulation and working
   memory during adolescence, and their influence in determining functional outcomes. IMPACT: Understanding the
   neural and physiological systems associated with working memory capacity and stress regulation in adolescence,
   and their contribution to CD severity, is a crucial step for elucidating the core pathophysiological mechanisms
   that promote the emergence and exacerbation of psychosis.
   
   Abstract: Adolescence is a peak time for the emergence of the core symptoms of psychopathology. Cognitive disorganization (CD) is a key symptom dimension of psychosis that emerges most commonly in adolescence, predicts the onset and severity of psychotic disorders, and transcends DSM diagnostic categories. Although little is known about the biological correlates of CD, adolescents experiencing disorganization have significant deficits in working memory capacity...
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2. 5/9-Predictors and Mechanisms of Conversion to Psychosis, NAPLS Consortium, National Institute of Mental Health (NIMH), 5U01 MH082004, 9/25/14-6/30/19.
   
   NIH Abstract: Schizophrenia and other forms of psychosis affect approximately 3% of the population with a disorder
   that is usually chronic and disabling. The peak age of onset is between ages 18-30, occurring just as life’s most
   productive years are beginning. Although genetic liability and abnormal brain development are known contributing
   factors, the etiology and pathophysiology of schizophrenia and related syndromes is largely unknown. To date,
   prospective observation of onset, i.e., the transition from vulnerability to disorder has not been possible because
   most persons at true risk cannot be identified premorbidly. This has hampered efforts at prevention. However, recent
   progress in risk ascertainment methodology has enabled reliable identification of help-seeking persons with pre-psychotic
   or “prodromal” clinical syndromes who develop psychosis within 1-2 years at rates between 20%-50%. Thus, clinical
   high-risk populations are now available for tracking prospectively the development and emergence of psychosis.
   However, because of the low incidence of schizophrenia and the heterogeneity of outcomes in clinical high-risk
   cases, single site studies cannot efficiently exploit the risk criteria in identifying predictors and mechanisms of
   psychosis. The NAPLS consortium was created to solve this problem. Eight NIMH-funded sites in North America studying
   prodromal patients using a common prodromal assessment instrument pooled data to create the largest sample of such
   persons worldwide (N=291), 35% of whom converted to psychosis after 2 years. An algorithm of baseline data was
   generated predicting psychosis with about 80% positive predictive power and 40% sensitivity. In this revised proposal,
   we describe a collaborative prospective study for which we will recruit 800 cases and 400 appropriate controls over 5
   years using common, standardized clinical and neurobiological measures. The aim is to collect a sample with sufficient
   size and power to rigorously test elements critical to the liability for and development of psychosis in the biomarker
   domains of brain structure, electrophysiology, stress hormones, and genomics, and in the clinical domains of prodromal
   presentation and epidemiology. The revised proposal addresses reviewers’ concerns, including the integration of the
   research plan and measures into a unifying framework. The findings will enhance our ability to identify persons at
   high risk for imminent psychosis, by refining predictors of conversion, and expanding our understanding of the
   underlying neural mechanisms. Such knowledge is critical for future efforts at early detection, intervention and
   prevention of psychotic disorders. PUBLIC HEALTH RELEVANCE: Preventing schizophrenia and other psychoses could relieve
   an enormous burden of personal and family suffering and economic losses to society. This 8-site project aims to
   increase our ability to identify high-risk individuals prior to onset and to pinpoint neurobiological changes that
   underlie the emergence of a psychotic disorder. These efforts are critical to the development of effective preventative
   intervention strategies for psychotic disorders.
   
   NIH Abstract: schizophrenia and other forms of psychosis affect approximately 3% of the population with a disorder that is usually chronic and disabling. The peak age of onset is between ages 18-30, occurring just as life's most productive years are beginning. Although genetic liability and abnormal brain development are known contributing factors, the etiology and pathophysiology of schizophrenia and related syndromes is largely unknown. To date, prospective observation of onset, i.e., the transition...
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3. Developmental Disabilities Research Core – Developmental Neuroimaging, 5 P30 HD003110, Core PI, NIH National Institute of Child Health and Human Development (NICHD), 9/24/2013 – 6/30/2018.
   
   The goal of this project is to provide educational, technical, training, and environmental support and resources for all projects in the Neurodevelopmental Disorders Research Center (DDRC) that have or plan on having a neuroimaging data acquisition or data analysis component.
   NIH Abstract: The primary aim of the Developmental Neuroimaging Core is to serve the interdisciplinary
   and translational research needs and goals of the DDRC. Advances in human and animal neuroimaging
   techniques provide the unique ability to gain insight into the neural circuitry and mechanisms
   underlying cognition, behavior and neural development in typically developing individuals and those
   with neurodevelopmental disorders. The strengths of in vivo neuroimaging techniques become
   particularly evident when included in longitudinal study designs that are particularly well suited
   for understanding the trajectories of developmental disorders. Neuroimaging studies offer the
   additional possibility of teasing apart the heterogeneity in complex, behaviorally-defined
   neurodevelopmental disorders, by providing insights into potential brain phenotypes for these
   conditions. Even more advanced methods are available for imaging the brain in animals. Genetic
   studies of neurodevelopmental disorders have led to the identification of a number of disease
   susceptibility genes and genetic engineering approaches have enabled the creation of genetically
   altered cells and animals (mice). Invivo multiphoton imaging of these animal and cellular models
   provides a unique avenue to study distinct aspects of nervous system development and function relevant
   to neurodevelopmental disorders. While conventional confocal microscopy can be used for high-resolution
   imaging of fluorescent labeling in fixed tissue, multiphoton laser imaging enables visualization
   and quantification of XFP filled neurons, glia, and axons in brain slices, or intact brains. Novel
   scanner technology and acquisition technology has also enabled the study of brain development in
   animal models via MRI, specifically for non-human primates and rodents. In 2002, the Developmental
   Neuroimaging Core (DNC) was established in response to the ever-increasing demand for structural and
   dynamic neuroimaging in humans and animals, and confocal and multiphoton imaging in animals. The DNC
   is of central importance to the research efforts of the DDRC. Our mission was to create a translational
   developmental neuroimaging core that would integrate science and research across cellular and systems
   levels of investigations, and facilitate interdisciplinary collaborations to address the needs of our
   DDRC investigators (Figure 1). Acquisition of data using magnetic resonance imaging and high-resolution
   microscopy, and the subsequent image analysis capacity necessary to analyze such data, requires a level
   of investment beyond the means of most individual investigators. Furthermore, this capacity can only be
   used fully with the assistance of a team of research scientists with extensive training and established
   expertise in the range of techniques required for modern neuroimaging approaches. To realize this
   mission, the core has been specifically configured to promote translational science and to forge
   interdisciplinary collaborations. During the past 5 years, the image analysis and tool development
   expertise of investigators in the MRI component of the DNC (codirected by Drs. Belger and Styner), and
   the cellular imaging expertise and infrastructure of the CMI component (co-directed by Drs. Polleux and
   Peterson), combined with the extensive expertise in image processing and graphics in computer science, have
   led to three major accomplishments: ¿ Translational neuroimaging research has flourished: The confocal
   and multiphoton components and the MRI components have developed and implemented new image processing tools
   for studying neurodevelopmental mechanisms from the cellular to the systemic level. As such, the DNC
   provides support for the development and implementation of imaging and image analysis methods that bridge
   research at the cellular level with research at the systems level, as applied to the studies of
   neurodevelopmental mechanisms and processes in humans, primates, rodents, and drosophila. ¿ Interdisciplinary
   collaborations have been forged between basic scientists, clinicians and computer scientists; integrating
   skills and expertise across disciplines and between previously divergent areas of science and scientists. ¿
   Groundbreaking tool developments and research advances have been made in the imaging of early brain
   development. This core has been structured to satisfy the criteria for the development and organization of
   cores described in the Introductory Overview. As such, the core services are of critical importance to the
   maximum number of investigators representing cutting-edge, high-quality scientific practice. The core services
   are cost-effective, as they provide access to unique computational resources and personnel expertise not
   available through other campus resources and that would be prohibitively expensive for individual DDRC
   investigators to develop or support through their own research grants. The DNC advances and promotes
   interdisciplinary and translational research, consistent with the mission of the Center. This Core further
   leverages existing University resources by partnering with other relevant Centers/Departments with key
   relationships to the DDRC (e.g., UNCNC, Psychiatry, Radiology, BRIG). In addition to providing research
   services, this core has a generative role: it creates new imaging methods, knowledge and image analysis
   tools otherwise not available to investigators in the Center, such as automated methods for diffusion tensor
   imaging based analysis, subcortical structure segmentation and cortical thickness analysis for both human
   and animal brain MRI data, from birth to age 4. This generative role is facilitated by the close interactions
   between the computer scientists, neuroanatomists and clinical researchers associated with the DNC. By
   providing support to both human and animal imaging studies this Core integrates methods within and across
   cores, to produce a whole that is substantially greater than the sum of the individual parts. The core
   integrates the expertise of clinical imaging researchers, statistical analysts, MR physicists, computer
   scientists, neuroanatomists and behavioral researchers, for the conduct of human neuroimaging. It further
   integrates image processing expertise available for human in vivo image analysis, for application to
   multiphoton/confocal microscopy. Finally, the DNC cost-effectively extends existing resources and improves
   research quality, by providing training (e.g.. training in image processing software for neuroimaging etc.)
   to DDRC investigators and laboratory staff.
   
   The goal of this project is to provide educational, technical, training, and environmental support and resources for all projects in the Neurodevelopmental Disorders Research Center (DDRC) that have or plan on having a neuroimaging data acquisition or data analysis component.
   NIH Abstract: The primary aim of the Developmental Neuroimaging Core is to serve the interdisciplinary and translational research needs and goals of the DDRC. Advances in human and animal neuroimaging...
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4. Neuroendocrine Mechanisms of Reproductive Hormone Related Affective Dysfunction, NIH National Institute of Mental Health (NIMH), Co-investigator, 9/13/2013 – 8/31/2016.
   
   Abstract: Affective disorders, such as postpartum depression (PPD) and other reproductive-related mood
   disorders, are common and constitute a significant burden for women, children, and society. However, little
   is known about the neurobiological mechanisms underlying depressive disorders in women. The long-term goal
   of this research is to 1) advance our understanding of the biological mechanisms underlying both the triggering
   of and susceptibility to depressive disorders in women; and 2) permit the prediction of those at risk for
   PPD. The objective of the current project is to examine whether those with a past episode of PPD (at “high
   risk” for recurrence) show differences in emotional arousal and reward processing domains relative to
   healthy control women (without a history of PPD) under baseline and hormone withdrawal-precipitated
   conditions. Our central hypothesis is that reproductive hormone changes are associated with dysregulation of
   the neural circuits underlying emotional arousal and reward processing and consequent depressive symptoms in
   high-risk women. The rationale for the proposed study is that employing a scaled down model of puerperal
   hormonal events in high-risk women permits the identification of a group of individuals homogeneous for
   reproductive related affective dysfunction and, hence, the best opportunity for disentangling the specific
   changes in brain function due to reproductive hormones from those accompanying reproductive hormone-precipitated
   affective dysfunction. Moreover, identifying a neurophysiologic biomarker for hormone-related affective
   dysfunction provides a clear pathway for examining mechanisms of susceptibility to affective dysfunction
   across disorders. We plan to accomplish the objectives of this application by pursuing the following specific
   aims: 1) to assess the effects of simulated postpartum reproductive hormone withdrawal, compared to baseline,
   on corticolimbic circuit activation in high-risk and control women; and 2) to examine the effects of
   reproductive hormone withdrawal, compared to baseline, on reward circuit activation in high-risk and control
   women. An additional exploratory aim is to identify a neural biomarker, characterized by corticolimbic and
   reward circuit dysfunction, that can be used to predict the onset of PPD. The proposed study involves experimentally
   manipulating reproductive hormones in euthymic women to create a scaled down version of the changes that occur at
   the puerperium. This endocrine manipulation paradigm will be used to examine the neurocircuitry underlying the
   regulation of affect and reward processing under baseline and hormone withdrawal-precipitated conditions among
   women who are expected to experience hormone-related affective dysregulation (n=15) and controls (n=15). The
   expected outcome is the identification of neural circuits underlying both the susceptibility to and mediation
   of hormone-related affective dysfunction. Understanding these neurobiological mechanisms will subsequently improve
   our ability to identify those at risk for PPD, which may strengthen prevention efforts and ultimately prevent the
   deleterious effects of maternal depression on offspring.
   
   Abstract: Affective disorders, such as postpartum depression (PPD) and other reproductive-related mood disorders, are common and constitute a significant burden for women, children, and society. However, little is known about the neurobiological mechanisms underlying depressive disorders in women. The long-term goal of this research is to 1) advance our understanding of the biological mechanisms underlying both the triggering of and susceptibility to depressive disorders in women...
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5. Neural Markers and Rehabilitation of Executive Functioning in Veterans with TBI and PTSD, US Army Medical Research, Co-investigator, 9/30/11-9/29/15.
   
   Abstract: Up to half of all military service members with combat-related traumatic brain injury (TBI)
   also suffer from Posttraumatic Stress Disorder (PTSD). TBI and PTSD are each associated with cognitive
   problems in what are called “executive functions” such as planning actions, inhibiting behavior, monitoring
   one’s own thoughts and feelings, and solving problems day-to-day. These types of impairments occur more often
   among veterans with both TBI and PTSD than among those with only one of these conditions. The combination of
   TBI and PTSD in veterans has also been linked to problems with anger and violence, which are common complaints
   of veterans seeking mental health services post-deployment and have been shown to predict poor treatment
   outcomes in Iraq and Afghanistan veterans. Although the relationship between combined TBI/PTSD diagnoses and
   post-deployment adjustment problems has been demonstrated, there has been little research into clinical
   interventions designed to reduce the severity of cognitive and affective symptoms in veterans with both TBI
   and PTSD. Therefore, we propose a randomized clinical trial involving a cognitive rehabilitation intervention
   that targets improved executive functioning, with the participation of N=100 veterans diagnosed with both TBI
   and PTSD (n=50 in experimental group and n=50 comparison). The intervention is both technologically and
   behaviorally based. All participants will receive an iPod touch. Control participants will be instructed to
   practice iPod touch applications to improve motor speed whereas experimental participants will be instructed
   to practice iPod touch applications that have shown to improve inhibitory control and self-monitoring behavior,
   which also includes an application to remind participants to practice planning skills. Family members in both
   groups will be trained as “mentors” to reinforce veterans’ use of the applications in everyday living
   environments. Trained facilitators will also travel to participants’ homes to meet with veterans and family to
   observe behaviors in the home environment, arrive at strategies for applying new skills in their situations,
   troubleshoot any iPod technical problems, and review family mentoring processes. We will measure clinical outcomes
   using a comprehensive array of functional and structural methods at baseline and six months. We hypothesize
   improved executive function among those in the experimental group as well as reduced irritability/impulsivity
   and improved social/occupational functioning. We further hypothesize that, as a group, veterans participating
   in the cognitive rehabilitation program will show significant changes in neural activity associated with executive
   functions when comparing pre- and post-treatment EEG and fMRI responses. Better understanding of the neural
   circuitry and neurocognitive function underlying executive function and associated affective control deficits
   in veterans with both TBI and PTSD, and how they relate to treatment outcome, will allow us to better identify
   therapeutic targets for cognitive rehabilitation. The current proposal aims to explore the relationship between
   brain function and connectivity in selective pathways/circuits, neuropsychological functioning, and cognitive
   rehabilitation response in veterans with both TBI and PTSD. This study of the neurobiology and neuropsychology
   associated with intervention efficacy will allow us to identify veterans with both TBI and PTSD who are
   predisposed to positive treatment outcomes. To our knowledge, this will be the first attempt to integrate
   neurobiological and neurocognitive techniques with information about the efficacy of a theoretically and
   empirically driven cognitive rehabilitation intervention in veterans with combined TBI/PTSD diagnoses. This
   research may suggest additional avenues for assessment of clinical intervention efficacy and the identification
   of therapeutic targets (e.g. alteration of function in fronto-limbi
   
   Abstract: Up to half of all military service members with combat-related traumatic brain injury (TBI) also suffer from Posttraumatic Stress Disorder (PTSD). TBI and PTSD are each associated with cognitive problems in what are called 'executive functions' such as planning actions, inhibiting behavior, monitoring one’s own thoughts and feelings, and solving problems day-to-day. These types of impairments occur more often among veterans with both TBI and PTSD than among...
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Foundation/Non-Profit/Association

1. Oxytocin Effects on Cocaine-Induced Maternal Neglect, Co-Investigator, Foundation of Hope for Research and Treatment of Mental Illness, 5/1/2015 – 4/30/2018.
   
   Abstract: We propose to study a promising new treatment which targets the negative effects that cocaine use
   during pregnancy has on mothering behavior. We focus on this topic because cocaine use is a persistent mental
   and physical health problem across the nation, and in North Carolina specifically, with ~ 2% of residents
   reporting use in rural, urban and suburban settings1. In the past decade cocaine use has increased dramatically
   in women of child-bearing age. Cocaine abuse during pregnancy is highly correlated not only with maternal
   depression, but also with rates of disorganized caretaking, and at its most extreme, with infant and child
   neglect and abuse 2-5. However, even without abuse, their children are at increased risk of physical, behavioral,
   psychiatric and academic problems,and of becoming drug abusers themselves,6 thus perpetuating the cycle across
   generations. Drug-related maternal neglect is the primary reason children are removed from the home, contributing
   to up to 90% of child placements in the overburdened welfare system7. In those who retain custody of their
   children (85%), research shows that early parental behaviors are the most powerful determinants of infants’
   cognitive, emotional, behavioral and physical development. The early postnatal environment, of which mother
   is the primary architect, appears to have at least as strong, if not stronger, effect on infant developmental
   trajectories as does in utero cocaine exposure 8. Improving maternal behavior during this critical time would confer
   long-lasting benefits to both mother and child. Although the actual causes of cocaine-related child neglect remain largely
   unknown, animal research suggests that cocaine ‘hijacks’ the brain systems that are naturally involved in the
   pleasure-inducing aspects of important social relationships such as mother-infant bonds. Drs. Grewen, Belger and
   Johns at UNC have been examining the underlying mechanisms of cocaine-induced maternal neglect as part of a program
   project studying both human and rodent mothers and infants. This allows more effective investigation of how the brain
   is changed by cocaine, and of how these changes relate to mothering-infant interactions. An important goal is to discover
   early treatments that will reduce the negative impact of prenatal cocaine on mothering behaviors. One possible new
   treatment is oxytocin, a natural molecule involved in childbirth and breastfeeding. However it also acts in the brain
   to promote important social bonds such as those formed between mother-infant,
   close friends and devoted partners. Oxytocin facilitates important social bonding in humans and other mammals.
   It is involved in reducing stress and anxiety, while promoting calmness, social approach and nurturing
   behaviors9-12 One way cocaine may interfere with mother-infant bonding is by disrupting the oxytocin system in the
   brain9,13-15. Rodent studies conducted by Dr. Johns and others indicate that cocaine use during pregnancy not only
   results in neglect of offspring, but also in lower levels of oxytocin in brain regions involved in maternal response to
   infants10,13,16-19. Studies by Dr. Grewen reveal that human mothers who use cocaine during pregnancy have impaired nurturing
   behavior, greater anxiety and irritability while interacting with infants, reduced oxytocin and greater stress hormones
   levels in blood. Dr. Pedersen has used the proposed intranasal oxytocin treatment to effectively and safely reduce anxiety,
   alcohol tolerance and withdrawal symptoms in alcohol-dependent men and women. Treatment with oxytocin blocks the stimulant
   effects of cocaine in rodents (sarnyai).To date there have been no studies of the effectiveness of oxytocin treatment
   on cocaine-induced maternal neglect. The proposed research would be the first to test whether short term postpartum
   oxytocin treatment can improve maternal response to infants. It is strengthened by complimentary study of both humans
   and rodents.
   
   Abstract: We propose to study a promising new treatment which targets the negative effects that cocaine use during pregnancy has on mothering behavior. We focus on this topic because cocaine use is a persistent mental and physical health problem across the nation, and in North Carolina specifically, with ~ 2% of residents reporting use in rural, urban and suburban settings1. In the past decade cocaine use has increased dramatically in women of child-bearing age. Cocaine abuse during pregnancy...
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2. Neural Basis Of Decision Making And Emotion Regulation Deficits In Post-traumatic Brain Disorder (PTSD), Principal-Investigator, Foundation of Hope for Research and Treatment of Mental Illness, 9/1/2014 – 8/31/2017.
   
   Abstract: The goal of this project is to characterize brain function and connectivity impairments associated
   with deficient cognitive control and emotion regulation in veterans with post-traumatic stress disorder
   (PTSD. It is estimated that up to half of all military service members with combat-related traumatic brain
   injury (TBI) also meet criteria for Posttraumatic Stress Disorder (PTSD). TBI and PTSD are both characterized by
   severe deficits in multiple cognitive domains, including attention, executive function, and affective and
   cognitive regulation. It has been shown that significant decision-making and executive function deficits,
   accompanied by disinhibition, occur more often among veterans with both TBI and PTSD than among veterans diagnosed
   with only one of these conditions. The combination of TBI and PTSD in veterans has also been linked to problems
   with emotional regulation such as anger and violence, which are common complaints of veterans seeking mental
   health services post-deployment and have been shown to predict poor treatment outcomes in Iraq and Afghanistan
   veterans. Cognitive control and executive dysfunction, especially difficulty with attentional processing, is
   strongly related to hostility and aggressiveness in Iraq and Afghanistan veterans, increasingly so in the presence
   of TBI and PTSD. The primary aim of this FOH proposal is to ADD a control group to a funded parent randomized
   trial of theoretically-based and empirically-supported cognitive rehabilitation aimed at improving cognitive
   and emotional control among Iraq and Afghanistan veterans with both TBI and PTSD. In the funded parent study are
   measuring clinical outcome and neurophysiological markers using well-validated neuroimaging protocols to
   demonstrate improved cognitive control, reduced irritability/impulsivity, and superior social/occupational
   functioning among those in the experimental group. The parent study does not have a non-PTSD/TBI comparison
   group, and specifically aims to assess improved neurocognition and changes in fronto-limbic neural circuits
   underlying cognitive control and affective reactivity as a function of clinical intervention. This add-on component
   is necessary to evaluate the relative cognitive and affective deficit of our PTSD veterans compared to a healthy
   population at baseline, prior to intervention. The funds from the FOH will support the recruitment and imaging
   of 20 healthy control subjects selected to be age-, gender, and socio-economic status matched to a group of
   well-characterized PTSD/TBI veteran participants from the DOD-funded parent study. Control subjects will be
   tested with the same imaging protocol as the parent study, including functional and structural imaging outcome
   measures (fMRI and DTI). The imaging session includes high-resolution anatomical scans, emotional face identification,
   working memory and inhibition-switch STROOP paradigms, as well as resting state and diffusion tensor imaging protocols.
   Image analysis will be conducted using FSL and tractography, and will focus on group differences in brain activation,
   as well as brain connectivity in frontal and limbic regions controlling executive capacity and emotion regulation.
   The proposed study is critical for interpreting and publishing results from the parent study examining the effects
   of a unique cognitive rehabilitation on executive function in patients with PTSD/TBI. The data form this add-on
   study will also be used for submission of a new collaborative R01.
   
   Abstract: The goal of this project is to characterize brain function and connectivity impairments associated with deficient cognitive control and emotion regulation in veterans with post-traumatic stress disorder (PTSD. It is estimated that up to half of all military service members with combat-related traumatic brain injury (TBI) also meet criteria for Posttraumatic Stress Disorder (PTSD). TBI and PTSD are both characterized by severe deficits in multiple cognitive domains, including...
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3. Neural Synchrony and Plasticity in Children with Autism, Principal-Investigator, Autism Speaks, 9/1/2014 – 8/31/2016.
   
   Abstract: Disrupted brain communication in autism spectrum disorder (ASD) is supported by an extensive literature
   of neuroimaging findings, as reflected in disrupted white matter microstructure and measures of functional
   connectivity (synchronization of activation across brain regions) as measured by functional magnetic resonance
   imaging (fMRI) (for a review, see Schipul et al., 2011), and has great potential to lead to a biomarker for the
   disorder. Unfortunately, very few fMRI studies include young children with ASD (Uddin et al., 2013), because of the
   challenge of remaining still and tolerating the scanner environment. Therefore, a gap exists in our understanding
   of brain synchronization development throughout childhood in individuals with ASD. Recently, techniques have
   been developed to analyze “neural synchrony” in electroencephalography (EEG) data (e.g. Donkers et al., 2013),
   and have been proposed to shed light on connectivity in autism (Uhlhaas, 2007). Because EEG is well tolerated
   in young and low-functioning children, such measures would be able to illuminate brain connectivity in ASD
   throughout development. Therefore, I propose to acquire the necessary training and collect data to implement
   neural synchrony analyses of EEG data to examine brain synchronization in children with ASD. Based on my previous
   findings of reduced adaptation in brain connectivity in ASD (Schipul et al., 2012), I will also explore the
   plasticity of EEG responses and synchrony in children with ASD in the context of a learning paradigm. I also
   propose to relate these measures of neural plasticity and synchrony to clinical measures of ASD symptoms to
   identify the potential of these measures as biological markers. Through this work I aim to develop the skills and
   expertise necessary to extend my research program, as well as expand the field’s understanding of brain connectivity
   and plasticity in ASD throughout development and its potential role as a biomarker for the disorder.
   
   Abstract: Disrupted brain communication in autism spectrum disorder (ASD) is supported by an extensive literature of neuroimaging findings, as reflected in disrupted white matter microstructure and measures of functional connectivity (synchronization of activation across brain regions) as measured by functional magnetic resonance imaging (fMRI) (for a review, see Schipul et al., 2011), and has great potential to lead to a biomarker for the disorder. Unfortunately, very few fMRI studies...
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Industry

Previous Grants/Projects

1. Perinatal Nicotine and Auditory Evoked Potentials in Early Infancy, NIH National Institute on Drug Abuse (NIDA), 1R21 DA031316, Co-investigator, through 2014.
   
   Abstract: Prenatal nicotine exposure (PNE) caused by maternal cigarette-smoking is linked to defects in
   auditory and visual sensory processing, behavior, memory, language, and generalized intelligence. Exposure
   to environmental tobacco smoke (ETS), in utero and early life is also related to neurocognitive deficits,
   behavioral disorders, and lower IQ measured in childhood and adolescence. The human brain undergoes massive
   growth, differentiation and maturation in utero and the first year of life, making it especially vulnerable to
   neurotoxic insult. Nicotine, a well-documented neural teratogen, crosses the placental and blood brain barriers
   to bind to nicotinic acetylcholine receptors, which are extensively involved in growth, connectivity and
   function of developing fetal and infant neural circuits. Thus PNE or ETS may have long term impact on neurochemical,
   neural circuitry, and behavioral development. Nicotine exposure from breast milk of smoking mothers or from breast
   milk of non-smoking mothers living with a smoker, may also contribute added nicotine exposure during early brain
   development. Quantification of infant nicotine levels from these multiple sources has been done in few studies,
   and fewer still have studied nicotine in association with very early brain and neurocognitive function. Methods:
   We propose to use auditory event-related potentials (ERP) in young infants with and without perinatal nicotine
   exposure, to study biological markers of neural aberration that may herald future neurocognitive deficits. We
   will examine sensory and higher order auditory cognitive processing in 3 groups of infants: 50 infants of mothers
   who smoke (PNE), 50 infants of non-smoking mothers living with a smoker (ETS), and 50 infants from smoke-free
   homes (CTL). We will measure biomarkers of nicotine exposure in maternal hair, urine and expired air, and in
   infant urine. We will use well- validated tools to estimate age-appropriate development focusing on items dependent
   upon auditory processing. A long term goal is to identify and refine a neurophenotype of nicotine’s detrimental
   effects on the developing brain, in order to inform early interventions in this important at-risk population. We
   plan to use acquired findings to support an application for more detailed, longitudinal study. PUBLIC HEALTH
   RELEVANCE: Cigarette-smoke in the home during pregnancy and early life are risk factors for poor performance on
   memory, language, attention and IQ tests later in childhood. In addition to all the other well known health risks
   of smoking, the hidden costs of nicotine-induced damage to early brain development may be particularly burdensome,
   starting before birth and lasting a lifetime. We propose to study brain activity in sleeping 4-month old infants,
   using state-of-the-art electrophysiological (EEG) techniques to compare the effects of maternal cigarette-smoking and
   second-hand smoke to smoke-free environments. We will measure nicotine exposure during pregnancy using a small sample
   of mothers’ hair, and nicotine exposure during early postpartum with by-products of nicotine in urine from infants
   and mothers. We will relate both to levels of brain activity and markers of neurocognitive development at measured
   at 4 and 12 months of age. To the extent that nicotine imposes damage to developing neural circuits, the effects on
   productivity, achievement and quality of life will be borne by the most vulnerable ‘involuntary smokers.’ Greater
   understanding of the early effects of nicotine on neural substrates of cognitive development will, therefore, provide
   public health benefit.
   
   Abstract: Prenatal nicotine exposure (PNE) caused by maternal cigarette-smoking is linked to defects in auditory and visual sensory processing, behavior, memory, language, and generalized intelligence. Exposure to environmental tobacco smoke (ETS), in utero and early life is also related to neurocognitive deficits, behavioral disorders, and lower IQ measured in childhood and adolescence. The human brain undergoes massive growth, differentiation and maturation in utero and...
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2. Assessing the Integrity of hte Brain’s Rhythm-Generating Networks in Infants at Familial High-Risk for Schizophrenia, Foundation of Hope, through 2014.
   
   Abstract: Two critical windows have been established in the pathophysiology of schizophrenia: a fetal and early infant
   period during which vulnerability is established and a later often adolescent or young adult period, during which
   conversion from vulnerability to psychosis occurs. The adolescent/young adult period has received a significant
   amount of scientific attention but perinatal brain form and function have not been directly investigated. Modern
   neuroscience based theories of schizophrenia propose that the perceptual, cognitive and affective impairments associated
   with this disorder may be related to a failure to integrate the activity of local and distributed neuronal circuits.
   Recent findings in cognitive neuroscience indicate that the rhythmic synchronization of neuronal discharges could provide
   the link within and between brain areas involved in a given network. During recent years disturbances in neural synchrony
   have been established as a major pathophysiologic feature of schizophrenia. The development and maturation of cortical
   networks critically depends on neuronal activity, whereby synchronized oscillations play an important role in the
   stabilization and pruning of connections. Therefore changes can be expected in the frequency and amplitude of oscillations
   as well as in the precision with which rhythmic activity can be synchronized over longer distances and different
   developmental stages. Aberrant neural oscillations during early critical periods may lead to imprecise temporal
   coordination of neural activity and result in the pathological modification of cortical circuits. Since behavioral
   impairments are already detectable in children who later develop schizophrenia, it is hypothesized that dysfunctional
   neuronal oscillation could cause aberrant early pre-and perinatal development, leading to maladaptive formation of
   cortical networks and faulty programming of synaptic connections. The goal of the current project is to develop a better
   understanding of the early brain changes associated with vulnerability to later schizophrenia by measuring neuronal
   synchrony through high density electrophysiological recordings in infants at high familial risk for schizophrenia and
   carefully matched control infants.
   
   Abstract: Two critical windows have been established in the pathophysiology of schizophrenia: a fetal and early infant period during which vulnerability is established and a later often adolescent or young adult period, during which conversion from vulnerability to psychosis occurs. The adolescent/young adult period has received a significant amount of scientific attention but perinatal brain form and function have not been directly investigated. Modern neuroscience based theories of schizophrenia propose...
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3. Sensory Experiences in Children with Autism: Study 4, National Institute of Child Health and Human Development (NICHD), 5R01 HD042168, through 2013.
   
   NIH Abstract: Unusual sensory experiences are reported in 69% of children with autism and these features are thought
   to have negative consequences on development, adaptive behavior, and family functioning. The purpose of this project
   is to explain the developmental course, functional impact, and pathogenesis of sensory features with implications for
   early detection and intervention. The project will study three commonly observed sensory response patterns:
   hyporesponsive, hyperresponsive, and sensory seeking. The aims are to: 1) determine longitudinal changes in sensory
   features in children with autism and DD; 2) measure how sensory features impact children’s adaptive behaviors (daily
   living, functional communication/social skills, and level of participation in home/community activities), maladaptive
   behaviors (stereotyped features, social-emotional problems), and family functioning (parental strain); and 3) isolate
   specific neurocognitive and contextual risk factors that are associated with the observable sensory problems. Four
   interrelated studies (total n=210) will address these aims. Study 1 (prospective longitudinal design) uses an existing
   cohort to examine stability of sensory features from the preschool (2-6 yrs) to the school-age (6-12 yrs.) period, and
   the functional impact of these features on child/ family outcomes. Study 2 employs retrospective video analysis to
   identify precursors of sensory features in children with autism during infancy (9-18 months), differentiate these from
   controls, and predict to preschool/school-age developmental outcomes. Study 3 uses a combination of lab measures,
   personal accounts of parents and verbal children, and in-home behavioral observations to determine the environmental
   contexts that elicit unusual sensory features and their impact on family functioning in daily life. Study 4 uses
   electrophysiology (ERP) to test neurocognitive mechanisms (sensory detection, discrimination, involuntary orienting)
   that are predicted to underlie specific sensory phenotypes. Thus, in a subgroup of children, convergent data from 4
   developmental time points (early infancy, later infancy, preschool and school years) will be secured to study change
   trajectories in sensory features in autism using mixed methods. Our findings may have implications for understanding
   brain-behavior linkages, early risk markers of unusual sensory features and their developmental course, and novel
   intervention strategies that may improve child and family functioning. [These aims are consistent with NIH Autism
   Research Matrix priorities #16, 19, 22, 23 & 26.] Project Narrative Relevance Although sensory problems such as
   under/over-reactions to sounds, touch, and visual stimuli are very common in children with autism and other
   developmental disorders, there is little research defining how these features change over time, what causes them
   to occur, and how much they negatively impact upon a child’s development, the parent’s well-being, and social
   participation. Because so little is known about sensory features in autism, families are vulnerable to myriad
   non-efficacious sensory-based treatments that purport cures for these issues. Findings from this study will address
   the above limitations in the literature and may have implications for understanding potential brain-behavior linkages,
   early risk markers of unusual sensory features and their developmental course, and novel intervention strategies
   aimed at improving child and family functioning.
   
   NIH Abstract: Unusual sensory experiences are reported in 69% of children with autism and these features are thought to have negative consequences on development, adaptive behavior, and family functioning. The purpose of this project is to explain the developmental course, functional impact, and pathogenesis of sensory features with implications for early detection and intervention. The project will study three commonly observed sensory response patterns: hyporesponsive, hyperresponsive, and sensory...
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4. Neural Circuitry of Social Cognition in the Broad Autism Phenotype, National Institute of Mental Health (NIMH), 5U01 MH082004, through 2013.
   
   NIH Abstract: For over 15 years, our research team has taken Kanner’s original observations about behavioral
   features characteristic of some parents of autistic individuals and developed standardized, valid, and reliable
   clinical measures to define what is now referred to as the Broad Autism Phenotype (BAP). The BAP is thought to
   represent the phenotypic expression of the underlying genetic liability to autism in non-autistic relatives of autistic
   individuals and is defined by characteristics that are milder but qualitatively similar to the defining features of
   autism. In our current UNC STAART Autism Research Center, we have identified abnormalities of social cognition (on
   tasks linked in previous studies to specific brain regions in the neural circuitry of social cognition) that occur
   more commonly in “autism parents” with the social behavioral characteristics of the BAP (i.e., aloof personality)
   than in either “autism parents” without aloof personality or community controls. We have developed fMRI paradigms
   that identify abnormalities in key components of the neural circuitry of social cognition in autism (amygdala, superior
   temporal sulcus, and fusiform gyrus) and developed a novel approach for probing the complex processing of social
   information from faces – the Bubbles Method that allows us to integrate simultaneous measurement of eye tracking data,
   skin conductance response, and BOLD responses on fMRI to isolate which features of the face drive behavioral,
   autonomic, and neural discrimination of social information from faces. In this revised application, we propose to use
   fMRI, neuropsychological, behavioral, and psychophysiological measures to characterize the neural circuitry of
   abnormal social cognition in parents of autistic individuals and to elucidate the stage of information processing
   at which dysfunctional social cognition arises in the BAP. This proposal is a collaboration of three investigators
   with a track record of collaboration and complementary experience in autism and the BAP (J. Piven at UNC), fMRI of
   social cognition (G. McCarthy at Duke), and novel approaches to elucidating the neural basis of social cognition (R.
   Adolphs at Caltech). Study of the behavioral and neural mechanisms underlying the social behavioral component of the
   BAP, as proposed in this application, will provide important new insights into the forme fruste of the autism brain
   and behavioral phenotype for use in future genetics, brain, and behavioral studies of autism and the BAP.
   
   NIH Abstract: For over 15 years, our research team has taken Kanner's original observations about behavioral features characteristic of some parents of autistic individuals and developed standardized, valid, and reliable clinical measures to define what is now referred to as the Broad Autism Phenotype (BAP). The BAP is thought to represent the phenotypic expression of the underlying genetic liability to autism in non-autistic relatives of autistic individuals and is defined by characteristics that are milder...
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5. Prospective Studies of the Pathophysiology of Schizophrenia – Project 2: Mapping Cortical Circuit Maturation in High Risk Adolescents, UNC Silvio O. Conte Center, 5R01 MH61603, Co-investigator, through 2013.
   The goal of this project is to identify pathogenic mechanisms in schizophrenia and related psychotic disorders using targeted gene strategies to develop  animal models and neurobiologic studies of high risk human subjects.
   
   NIH Abstract: The goal of this project is to map the maturation of cortical circuits and higher-order
   cognitive functions in children and adolescents at genetic risk for schizophrenia. Executive function
   and social-affective processing deficits are present in both individuals with schizophrenia and in
   those at genetic-high-risk (GHR) for the illness, and as such they represent cognitive endophenotypes
   of schizophrenia. Nevertheless, their characteristics in younger GHR individuals, the timing of their
   onset, and the specific neurodevelopmental mechanisms that accompany them are not known. Puberty is a
   critical period both for the maturation of these functions, and for the onset of psychosis. The proposed
   study will probe functional and structural change that accompany peripubertal brain maturation in genetic
   high risk individuals, and will investigate executive control and social-affective processes in GHR
   children and adolescents. We’ will probe attention and executive and affective processing in
   fronto-striate-limbic regions in 60 GHR and 60 healthy subjects aged 9-18 using. We will use a multimodal
   assessment protocol, including (a) neurocognitive testing (b) functional magnetic resonance imaging
   (fMRI), (c) electrophysiological recordings (ERPs), and (d) structural and diffusion imaging (sMR| and DTI).
   In Specifc Aim 1, we will compare the neurocognitive profile of genetic high risk (GHR) children and
   adolescents to healthy subjects cross-sectionally, and further assess group differences in their maturational
   trajectory with longitudinal follow-ups. Specific Aim 2 will characterize the functional profile of
   fronto-striate-limbic regions in GHR children and adolescents, using functional magnetic resonance imaging
   and electrophysiological recordings. The structural profile of fronto-striate-limbic regions in GHR
   adolescents, including both gray matter and white matter properties, will be assessed in Specific AIMS.
   Finally, Specific AIM 4 will focus on network level integrative functioning of fronto-striate and fronto-
   limbic circuitry in GHR children and adolescents by exploring associations between functional connectivity
   measures, white matter properties and neurocognitive measures. By bringing together a strong clinical high-
   risk research program and a well established and diverse research infrastructure, this project promises to
   unveil critical knowledge about the neurodevelopmental changes associated with genetic risk for schizophrenia.
   The proposed experiments are novel, timely and highly significant for they focus on a unique population and
   probe a unique stage of cortical development that is critical for understanding the pathophysiology of core
   neurocognitive deficits in schizophrenia.
   
   NIH Abstract: The goal of this project is to map the maturation of cortical circuits and higher-order cognitive functions in children and adolescents at genetic risk for schizophrenia. Executive function and social-affective processing deficits are present in both individuals with schizophrenia and in those at genetic-high-risk (GHR) for the illness, and as such they represent cognitive endophenotypes of schizophrenia. Nevertheless, their characteristics...
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6. Neurobiology of Selective Attention in Schizophrenia, 1R01MH58251-01A3, PI (NIMH), through 2013.
   The clinical objective of the proposed studies is to relate selective attention deficits in schizophrenia to symptomatology and chronicity of this illness.
   
   NIH Abstract: Attention disturbances have been described as core deficits underlying global cognitive
   dysfunction in schizophrenia. These deficits appear prior to illness onset, are observed
   in unaffected relatives, and are highly susceptible to emotional interference. This proposal
   has two broad aims that extend our previous studies on attention in schizophrenia:
   (1) To characterize the functional neuroanatomy of involuntary and voluntary attention
   processes in schizophrenia, and assess their disruption by affective interference and
   (2) To evaluate whether genetic high-risk individuals with prodromal symptoms (GHRP)
   show impairments in these domains of attention, thus exploring their potential significance
   as clinically relevant “risk markers” in vulnerable populations. We will use functional magnetic
   resonance imaging (fMRI) to map the spatial localization of the neural activity associated with
   attention processes in the brain, electrophysiological recordings to gather temporal information
   as to whether these deficits occur at the sensory or cognitive stages of processing, and performance
   indicators of target discrimination and distractor interference. This project has three specific
   aims. In Aim1, we will characterize the neural and hemodynamic correlates of VOLUNTARY attention in
   recent onset schizophrenia (roSCZ) and GHRP individuals. FMRI will probe the integrity of
   fronto-striate, fronto-temporal and fronto-parietal circuitry during a voluntary attention task,
   while ERP measures will assess N2/P3 component characteristics during the same task. In Aim 2, we
   will characterize the neural and hemodynamic correlates of EMOTIONAL INTERFERENCE during the
   deployment of VOLUNTARY attention processes in roSCZ and GHRP individuals. FMRI measures will
   assess fronto-limbic and fronto-striate activations and interactions, while ERP measures will
   characterize the novelty N2/P3 components elicited by the task-irrelevant emotional stimuli. In
   Aim 3, we will evaluate the neural and hemodynamic correlates of INVOLUNTARY attention in roSCZ and
   GHRP individuals, and determine whether these deficits are independent of global attention limits by
   manipulating the complexity of the primary task. Secondary aims will evaluate diffusion tensor
   imaging (DTI) and time-frequency domain EEG measures to inform whether co-existing alterations in
   white matter properties or local cortical neural synchrony may lend support to the “functional
   dysconnectivity” model of schizophrenia. The use of converging evidence from multiple methodologies
   as proposed in this project is highly innovative and can help us build a more complete model of the
   pathophysiological mechanisms underlying schizophrenia. Furthermore, this project is highly
   significant, as it aims to identify clinically relevant risk markers in vulnerable populations.
   
   NIH Abstract: Attention disturbances have been described as core deficits underlying global cognitive dysfunction in schizophrenia. These deficits appear prior to illness onset, are observed in unaffected relatives, and are highly susceptible to emotional interference. This proposal has two broad aims that extend our previous studies on attention in schizophrenia: (1) To characterize the functional neuroanatomy...
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7. A longitudinal EEG study of infants at risk for autism: Network Capacity Building (Phase I), Autism Speaks, Co-Investigator, 2/1/2013 – 8/31/2013.
   
   Abstract: This application proposes to add electroencephalographic (EEG) data collection to an NIH funded competing
   continuation of an Autism Center of Excellence (ACE) Network grant. We propose to add a multi-site EEG study to the
   ACE Network in two phases: during Phase I we will perform an 8-month feasibility project demonstrating the capacity
   of the network to perform a large scale, multi-site EEG study. During Phase II we will add EEG measurements to all
   scheduled visits (3, 6, 9, 12, 15, 24 months) for the remaining length of the grant. This application pertains to the
   Phase I project only. During this first phase we will set up and calibrate EEG systems at all sites, undertake net
   application and EEG data collection training, gather EEG data on a small set of subjects at each site (at the 6 month
   visit), establish quality control (with traveling phantoms), develop the database system, undertake data processing,
   and perform basic analyses. The ACE Network parent grant proposes a prospective, longitudinal study employing
   multi-dimensional behavioral assessments, structural MRI (sMRI) and diffusion tensor brain imaging (DTI) of 200 high
   and 60 low risk (for autism) infants at multiple points between 3 and 24 months. Data will be collected across 4 clinical
   sites around the U.S. The over-arching aim is to clarify early brain and behavior trajectories prior to the age when
   autism is traditionally diagnosed while it provides a unique opportunity to understand the neurobiological basis of
   autism and has to the potential to identify early risk markers during a period of post-natal brain plasticity when
   children may benefit maximally from early detection and intervention. Previous results from our initial ACE Network
   grant (2007-2012) revealed that high risk (HR) infants who go on to have autism at 24 months have impairments in visual
   orienting and motor behavior at 6 months of age, which may lay the foundation for the emergence of the defining
   features of autism (social deficits, repetitive behaviors) observed in these same infants by 12 months of age. Aberrant
   white matter tract development was detectable by 6 months of age in infants classified as autistic at 24 months (1),
   with further widespread abnormalities in white matter tract development and an increased rate of brain volume growth
   observed over the 6-24 month period. These results, for the first time, established that such brain changes occur
   concurrently with the emergence of behavioral abnormalities in ASD. Taken together, these findings point to brain and
   behavior changes during the 1st year (and as early as 6 months of age) as being critically important in the onset and
   development of autistic behavior. In the competing continuation of the ACE Network grant (2012-2017) we will follow up
   these findings by conducting earlier (3 months), more frequent (3, 6, 9, 12, 15, 24 months) and more in depth examination
   of the trajectories of brain and behavior development in HR and LR infants. By adding an EEG component to the ACE Network
   assessment battery we aim specifically to: (a) identify an inexpensive, early brain marker that could be integrated into
   a prediction model for early detection of autism; and (b) more fully understand brain-behavior relationships during the
   critically important period preceding and coinciding with the emergence of the defining features of autism.
   
   Abstract: This application proposes to add electroencephalographic (EEG) data collection to an NIH funded competing continuation of an Autism Center of Excellence (ACE) Network grant. We propose to add a multi-site EEG study to the ACE Network in two phases: during Phase I we will perform an 8-month feasibility project demonstrating the capacity of the network to perform a large scale, multi-site EEG study. During Phase II we will add EEG measurements to all scheduled visits (3, 6, 9, 12, 15, 24 months) for the remaining...
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8. Perinatal Nicotine and Auditory Evoked Potentials in Early Infancy, NIH National Institute on Drug Abuse (NIDA), Co-Investigator, 3/15/2012 – 2/28/2015.
9. Stress Effects on Executive Function in Individuals with Schizophrenia and Familial High Risk, National Alliance Res on Schizophrenia and Depression (NARSAD), 7/15/2011 – 7/14/2013.
   
   Abstract: Stress has been found to both trigger and exacerbate symptoms of schizophrenia, and it has been
   suggested that greater susceptibility to stress may explain some of the cognitive difficulties experienced
   by individuals with schizophrenia. Previous findings have indicated that during demanding cognitive tasks,
   the function of prefrontal cortex circuits is altered in both individuals with schizophrenia and in individuals
   with familial high risk (FHR) via a first-degree affected family member. While the response to stress may be
   a critical factor in mediating both cognitive and neural changes in schizophrenia, the mechanisms underlying
   these changes are not well-understood. It is currently unknown whether stress effects that may be elicited
   during a demanding task may influence the function of these neural pathways differently in individuals with
   schizophrenia, and whether changes in sensitivity to stress might reflect a risk factor that can be observed in
   individuals with FHR. The primary aim of the proposed study will be to use functional neuroimaging to assess
   how neural activation in prefrontal cortical circuitry is modulated by stress, and whether individuals with
   schizophrenia and familial risk show differences in these neural interactions. Well-established functional MRI
   techniques will be used to test activation in prefrontal circuits during performance of an executive function
   task with a concurrent stressor stimulus, in addition to behavioral and physiological measures of anxiety and
   stress reactivity. We will recruit 15 individuals with recent-onset schizophrenia, 15 individuals with FHR for
   schizophrenia and 15 matched controls for participation in the study. For the executive function task,
   participants will view a series of 4-digit numbers presented sequentially on a computer screen, and will indicate
   with a button press whether the number presented matches or does not match the one presented on the previous
   trial (1-back) or two trials ago (2-back). During half of the experiment, a stressor will be administered in
   the form of white noise at 100 dB, contrasted with blocks where lower noise will be presented at 85 dB. The
   central hypothesis of the proposed project is that the prefrontal response to stressors will be differentially
   modulated in both individuals with schizophrenia and in unaffected family members. We hypothesize that the
   group with schizophrenia will show the most severe disruption of executive function during stress, with reduction
   in prefrontal cortical circuit activity supporting these functions. We furthermore expect that the individuals
   with FHR will show an intermediate level of susceptibility to stress compared to the controls and the group with
   schizophrenia, with significantly greater stress-related disruption of prefrontal activity compared to controls.
   This proposed research is expected to enhance our understanding of how stress may contribute to the cognitive
   difficulties in schizophrenia, and whether changes in these mechanisms may reflect a risk marker for the disease.
   If the stress effects on prefrontal circuitry differ in individuals with familial risk, it is likely to be an
   important genetically-mediated intermediate phenotype of interest, further warranting future exploration of the
   specific genetic variants that may underlie these changes.
   
   Abstract: Stress has been found to both trigger and exacerbate symptoms of schizophrenia, and it has been suggested that greater susceptibility to stress may explain some of the cognitive difficulties experienced by individuals with schizophrenia. Previous findings have indicated that during demanding cognitive tasks, the function of prefrontal cortex circuits is altered in both individuals with schizophrenia and in individuals
   with familial high risk (FHR) via a first-degree affected...
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10. Identifying Discrete In Vivo Biobehavior Markers for Schizophrenia by Using a Novel Learned Irrelevance Paradigm in Conjunction with Electrophysiological and Functional Neuroimaging Techniques, National Alliance Res on Schizophrenia and Depression (NARSAD), 1/1/2010 – 12/31/2013.
    
    Abstract: One of the key deficits described in schizophrenia is the inability to ignore or filter out irrelevant
    stimuli, and it has been argued that the major abnormalities in schizophrenia can be derived from this single
    underlying deficit. A powerful behavioral task paradigm to study an organisms’ capacity to ignore irrelevant stimuli
    is the learned irrelevance (LIRR) paradigm. In this project we propose to use the LIRR paradigm in conjunction with
    a combination of brain imaging methods in order to identify specific and sensitive early risk factors for
    schizophrenia. We will use the high temporal resolution of event-related potentials (ERPs) to investigate the different
    subcomponents involved in LIRR in healthy controls and in individuals at ultra high risk for developing schizophrenia.
    Because ERPs do not permit a precise localization of the participating cortical areas, we will also use functional
    magnetic resonance imaging (fMRI) to identify the structural correlates of the processes involved in LIRR. We
    hypothesize that characterizing the neural mechanisms underlying LIRR in more detail will result in discrete in
    vivo biobehavioral markers for schizophrenia. This in turn may aid in the development of early intervention
    strategies designed to prevent or delay the onset of schizophrenia.
    
    Abstract: One of the key deficits described in schizophrenia is the inability to ignore or filter out irrelevant stimuli, and it has been argued that the major abnormalities in schizophrenia can be derived from this single underlying deficit. A powerful behavioral task paradigm to study an organisms’ capacity to ignore irrelevant stimuli is the learned irrelevance (LIRR) paradigm. In this project we propose to use the LIRR paradigm in conjunction with a combination of brain imaging methods in order to identify specific...
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11. The Relationship between Sensory Processing Abnormalities and Attention Deficits, National Alliance Res on Schizophrenia and Depression (NARSAD), through 2012.
    
    Abstract: Although unusual processing of incoming relevant or irrelevant stimuli in autism results in severe
    abnormalities in social behavior, the mechanism underlying such phenomena, a link between the sensory abnormalities
    and impaired executive function (such as working memory and selective attention) as well as the possible relationship
    between these and the development of social deficits remain unclear. The main goal of this project is to combine the
    high spatial resolution of functional magnetic resonance imaging (fMRI) with the high temporal resolution of
    event-related potentials (ERP) to compare neural activations evoked by task-irrelevant (simple tone and complex sounds
    with high alerting value, such as a siren) stimuli in simple oddball tasks and also by varying working memory loads.
    We hypothesize that neural activation to task-irrelevant complex novel environmental sounds will be smaller in
    individuals with autism compared to the control subjects and decrease more as a function of demands of the primary
    working memory task in individuals with autism. However, activations to pure tones will be similar in both groups
    during both working memory tasks. We also hypothesize that the Autism-Spectrum Quotient (Baron-Cohen et al., 2006),
    quantifying autistic traits in individuals, will be negatively correlated with the degree of frontal activations to
    task-irrelevant complex auditory stimuli. Neither ERP nor fMRI studies have examined the effect of complex environmental
    sounds with high alerting value (such as a siren) and also attentional modulation of neural activity elicited by
    task-irrelevant pure tone and complex novel environmental sound in autism. Moreover, there is no data regarding the
    mechanism of attentional modulation in dlPFC are related to autistic trait score. This is the first study that tests
    whether attentional resource availability affects the processing of task-irrelevant auditory stimuli (simple tone and
    complex novel sound) during a working memory task as a primary task with two difficulty levels. Studying whether the
    processing of unattended auditory stimuli is modulated by attentional demands and resource availability will provide
    new insights regarding auditory sensory abnormalities and attention deficit in autism.
    
    Abstract: Although unusual processing of incoming relevant or irrelevant stimuli in autism results in severe abnormalities in social behavior, the mechanism underlying such phenomena, a link between the sensory abnormalities and impaired executive function (such as working memory and selective attention) as well as the possible relationship between these and the development of social deficits remain unclear. The main goal of this project is to combine the high spatial resolution of functional magnetic resonance...
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12. Function BIRN (Biomedical Informatics Resource Network), Sub-Investigator (NIH), 12/1/2009 – 11/30/2011.
    
    The goal of this grant is to fund a national infrastructure for large scale, multi-center studies of brain functions using functional magnetic resonance imaging (fMRI).
    Abstract: The overarching goal of the Function BIRN (FBIRN) is to develop technology and methods, to conduct robust,
    reliable multi-center functional imaging studies, and to produce a knowledge base that would not otherwise be
    available through single-site imaging studies. The technology includes the development and refinement of multi-site,
    functional imaging protocols using robust cognitive tasks; the development and refinement of algorithms to reduce
    inter-site variability; the use of federated, distributed databases and storage; flexible and robust image processing
    software integrated with these databases and storage infrastructure; tools for data querying across the distributed
    databases to extract subsets of data from multiple sources; and the development of both classical statistical and datamining
    methods to reveal the patterns of imaging, clinical, and genetic data which differentiate important data clusters, such
    as novel population subtypes. To meet this goal, the FBIRN has chosen to develop the capacity to conduct a multi-center
    fMRI study in a focused group of subjects with a neuropsychiatric disorder, patients with schizophrenia. The lessons
    learned, the statistical methods developed, and the informatics structure constructed will be generalizable and applicable
    to a wide variety of clinical investigations. The test of the ability to combine subsets of clinical, functional imaging,
    and genetic datasets from disparate sites to form novel datasets will be the application of the methods to unique patient
    subtypes from the various sites to verify the course of the disease both cross-sectionally and longitudinally. The research
    plan includes the development of the technologies listed above in the service of identifying endophenotypes that reveal
    underlying dimensions of illness in schizophrenia drawing upon clinic characteristics (such as symptoms, gender), genetic
    background, course of illness (age of onset, premorbid adjustment, historical response to treatment), cognitive performance
    and brain activation.
    
    The goal of this grant is to fund a national infrastructure for large scale, multi-center studies of brain functions using functional magnetic resonance imaging (fMRI).
    Abstract: The overarching goal of the Function BIRN (FBIRN) is to develop technology and methods, to conduct robust, reliable multi-center functional imaging studies, and to produce a knowledge base that would not otherwise be available through single-site imaging studies. The technology...
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13. Multimodal Imaging of fronto-striate circuits in inviduals at Ultra High-risk for schizophrenia: In search of intermediate phenotypes, NARSAD Independent Investigator Award (PI), through 2011.
    The goal of this study is to use Functional Magnetic Resonance Imaging (fMRI) to characterize cortical pathology associated with the ultra high-risk for schizophrenia in prodromal and sympotomatic individuals to identify measures that can be used for early intervention strategies designed to prevent the onset of schizophrenia.
14. Human Functional Brain Anatomy (PPG), 1P01NS41328-01, PI (NINDS), through 2011.
    This Program Project will investigate the functional neuroanatomy of the human brain using high-field functional magnetic resonance imaging
    (functional MRI). The four scientific projects are strongly linked by their focus on the relationship between brain and behavior. The projects are organized into a logical progression from sensory processing through response.
15. Search for Brain Biobehavioral Markers of Schizophrenia: Clinical, Electrophysiological, and NeuroImaging, Foundation of Hope, through 2010.
    
    Abstract: The goal of this project is to map the maturation of cortical circuits and higher-order
    cognitive functions in children and adolescents at genetic risk for schizophrenia. Executive function
    and social-affective processing deficits are present in both individuals with schizophrenia and in those at
    genetic-high-risk (GHR) for the illness (i.e. with a first degree family member with schizophrenia). As such,
    these cognitive deficits may represent intermediate behavioral measures that can help us link the clinical
    symptoms of schizophrenia to underlying biological and genetic factors. Despite being promising markers, their
    characteristics in younger GHR individuals, the timing of their onset, and the specific neurodevelopmental brain
    mechanisms that accompany them are not known. Adolescence is a critical period both for the maturation of these
    functions, and for the onset of psychosis. The proposed study will probe functional and structural change that
    accompany adolescent brain maturation in genetic high risk individuals, and will investigate executive control and
    social-affective processes in GHR children and adolescents. We will probe attention and executive and affective
    processing in fronto-striate-limbic regions in 20 GHR and 20 healthy subjects aged 9-18 using. We will use a multimodal
    assessment protocol, including (a) neurocognitive testing (b) functional magnetic resonance imaging (fMRI), (c)
    electrophysiological recordings (ERPs), and (d) structural and diffusion imaging (sMRI and DTI). In Specifc Aim 1,
    we will compare the neurocognitive profile of genetic high risk (GHR) children and adolescents to healthy subjects
    cross-sectionally, and further assess group differences in their maturational trajectory with longitudinal
    follow-ups. Specific Aim 2 will characterize the functional profile of frontal and limbic regions in GHR children
    and adolescents, using functional magnetic resonance imaging and electrophysiological recordings. Finally, the
    structural profile of fronto-limbic regions in GHR adolescents, including both gray and white matter properties
    will be assessed in Specific Aim 3. We will further examine network level integrative functioning of frontal and
    limbic circuitry in GHR children and adolescents by characterizing associations between functional connectivity
    measures, properties of connective white matter fibers, and neurocognitive measures. By bringing together a strong
    clinical high-risk research program and a well established and diverse research infrastructure, this project promises
    to generate critical knowledge about the neurodevelopmental changes associated with genetic risk for schizophrenia.
    The proposed experiments are novel, timely and highly significant for they focus on a unique population and probe a
    unique stage of cortical development that is critical for understanding the pathophysiology of core neurocognitive
    deficits in schizophrenia. Support from the Foundation of Hope will provide resources critical for the continuation
    of this line of research and will bridge funding during the competing renewal of our UNC Conte Center for research
    on schizophrenia.
    
    Abstract: The goal of this project is to map the maturation of cortical circuits and higher-order cognitive functions in children and adolescents at genetic risk for schizophrenia. Executive function and social-affective processing deficits are present in both individuals with schizophrenia and in those at genetic-high-risk (GHR) for the illness (i.e. with a first degree family member with schizophrenia). As such, these cognitive deficits may represent intermediate behavioral...
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16. The Role of GABRA4 In The Pathophysiology of Autism, Autism Speaks, through 2009.
    
    Abstract: The proposed study, The Role of GABRA4 In The Pathophysiology of Autism, aims to develop a translational
    autism research program by building on the already established nationally recognized center for clinical autism
    research at UNC Chapel Hill. Our goal is to draw on the wonderful tradition of the clinical autism research program
    and integrate it with the skills of established basic scientists. To achieve this, we propose to utilize non-invasive
    human neuroimaging to investigate limbic system functioning and combine it with animal research to see if the
    variations in the limbic system may be due to altered GABAA receptor function. We propose to perform functional magnetic
    resonance imaging (fMRI) on autistic individuals while they perform a target detection task in which they are presented
    with blocks of visual stimuli from one of four categories: neutral scrambled pictures, aversive pictures, social
    pictures (faces), and circles with embedded targets. We will then investigate how GABAA 4 receptor subunit (GABRA4)
    knockout mice behave on tests of social interaction and social novelty in order to probe the role of the GABAA 4
    receptor in social behaviors. Additionally, we will utilize a new 9.4T animal MRI facility to investigate how loss of
    the GABAA 4 receptor alters amygdala structure. The primary goal of the proposed study is to train Kimberly
    Hills-Carpenter, a pre-doctoral candidate in the Neurobiology Curriculum at UNC-Chapel Hill, as a translational autism
    researcher with specializations in human neuroimaging and animal pharmacology so that she may achieve her future goal
    of becoming a tenure track principal investigator with a laboratory that specializes in translational autism research.
    
    Abstract: The proposed study, The Role of GABRA4 In The Pathophysiology of Autism, aims to develop a translational autism research program by building on the already established nationally recognized center for clinical autism research at UNC Chapel Hill. Our goal is to draw on the wonderful tradition of the clinical autism research program and integrate it with the skills of established basic scientists. To achieve this, we propose to utilize non-invasive human neuroimaging to investigate limbic system functioning and combine...
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17. The neural influence of affective dysregulationon executive function in unipolar major depression, National Alliance Res on Schizophrenia and Depression (NARSAD), through 2008.
    
    Abstract: Emotions are complex systems that developed to prepare an organism to act appropriately in response to
    environmental stimuli and challenges. The core symptoms of Major Depressive Disorder (MDD) strongly implicate emotional
    dysfunction (i.e., sadness and anhedonia), and MDD is characterized by hyper-responsiveness and protracted reactions to
    sad stimuli, particularly during the offset stage after the termination of a sad stimulus, relative to individuals
    without depression. Emotional reactivity is mediated through limbic circuits (e.g., the amygdala) that have extensive
    dopaminergically-mediated inhibitory prefrontal modulatory projections, and there is converging neuroimaging evidence
    that MDD is characterized by both limbic and prefrontal dysfunction. Interestingly, however, although there is evidence
    of top-down cognitive control of emotions in both nonclinical populations and MDD, there is surprisingly little data
    that addresses the bottom-up effects of limbic dysfunction on prefrontal functioning in MDD. The paucity of data
    addressing the effects of limbic dysfunction on prefrontal functioning in this patient population is particularly
    noteworthy given that individuals with MDD demonstrate impaired executive function abilities that have been linked to
    decreased activity in the prefrontal cortex and that remain impaired after disease remission. Therefore, given that,
    (1) MDD is characterized by protracted responses to sad events; (2) sad events activate the limbic system; and (3) the
    limbic system has inhibitory connections with the dorsal prefrontal executive system, we hypothesize that, in MDD,
    protracted limbic responses to sad stimuli will cause inhibited dorsal prefrontal recruitment in response to executive
    functioning stimuli soon after the offset of a sad stimulus. Such a pattern of results would have implications for how
    the effects of affective dysregulation in depression extend beyond responses solely to emotional stimuli but impact the
    much broader ability to achieve motivationally salient goals critical for effective functioning.
    
    Abstract: Emotions are complex systems that developed to prepare an organism to act appropriately in response to environmental stimuli and challenges. The core symptoms of Major Depressive Disorder (MDD) strongly implicate emotional dysfunction (i.e., sadness and anhedonia), and MDD is characterized by hyper-responsiveness and protracted reactions to sad stimuli, particularly during the offset stage after the termination of a sad stimulus, relative to individuals without depression. Emotional reactivity is mediated through limbic...
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18. Gene-Brain-Behavior in Autism, 1 U54 MH066418-01, Project PI (NIH/NIMH), through 2007.
    This grant focuses on conducting fMRI/Longitudinal MRI studies of
    social/affective processes and executive function/ritualistic-repetitive
    behaviors in adults and very young children with autism.
19. The role of dopamine in normal brain function, Foundation of Hope (PI), through 2007.
    This grant will use Functional Magnetic Resonance Imaging (fMRI) to characterize to understand the dopamine effects in normal healthy subjects.
20. Cortical function in Schizophrenia: Prodrome and First Episode, Foundation of Hope (PI), through 2005.
21. Functional Neuroimaging in Turner Syndrome, National Institute of Child Health and Human Development (NICHD), through 2004.
22. ERP and FMRI Correlates of Executive Cognitive Deficits and Symptomatology in Schizophrenia, National Alliance Res on Schizophrenia and Depression (NARSAD), through 2002.
23. Risperidone effects on frontal and temporal cortical function in schizophrenia patients undergoing fMRI cognitive performance, JANSSEN Pharmaceuticals (PI), open ended.
    For this project, we will compare the therapeutic efficacy of Risperidone and Olanzapine and the potential for neuroprotection in psychosis patients using measures of outcome such as psychopathology, neurocognition and MRI.