Mark T. Wallace - US grants

DESCRIPTION: The broad, long-term objective of the proposed work is to understand the neural substrates of cortical multisensory processing, for it is these circuits that undoubtedly play an integral role in binding information from the different senses into a coherent perceptual whole. The emphasis of the previous grant period has been on detailing the development of multisensory cortical circuits and their plastic potential during early postnatal life, and we will continue to expand on this theme in the current work. In addition, we will focus on characterizing the functional circuitry that forms the basis for cortical multisensory processes, an essential yet unrealized step toward a better understanding of how our perceptual gestalt is created. The work will continue in the cat model, in which a substantial foundation of knowledge exists, facilitating the completion of the proposed studies. The work is divided into three specific aims. In the first, a combined anatomical and physiological approach will be employed in an effort to detail the functional architecture of cortical multisensory circuits. This work will represent the first systematic attempt to describe how multisensory networks in the cerebral cortex are assembled. In the second aim, the fine spatial architecture of cortical multisensory receptive fields will be detailed, and the hypothesis that receptive field structure and heterogeneity plays a critical deterministic role in multisensory interactions will be tested. These studies will be done in the awake and behaving animal in an effort to better understand the functional role of multisensory cortex. These experiments will seek to identify and describe a previously unrecognized level of complexity and flexibility to multisensory processes. In the final aim, the capacity of the adult brain for multisensory plasticity will be examined. Although it is clear from psychophysical studies that such capacity exists, virtually nothing is known about the neural substrates that likely form the basis for these changes. The ultimate goal of this work dovetails well with the mission of the National Institute of Mental Health (through whom this work has been previously funded), in that it seeks to further our basic science understanding of the brain bases of multisensory-mediated behavior and perception, with the ultimate goal of translating this knowledge into useful clinical strategies and interventions. In this regard, it is becoming increasingly clear that a number of clinical neurologic disorders with a sensory component (e.g., attention deficit hyperactivity disorder, autism spectrum disorder, developmental dyslexia) may have preferential deficits in multisensory processing, and that both diagnostic and remediation strategies founded on a multisensory platform may provide more effective outcomes for individuals suffering with these conditions. PUBLIC HEALTH RELEVANCE The proposed work has great relevance in both the basic science and clinical arenas. An improved understanding of multisensory cortical processing is an essential step toward a more complete understanding of the brain bases of behavior and perception. Such knowledge will be of tremendous utility in the public health arena, in that it can be applied toward the development of more sensitive diagnostic tools, as well as more effective remediation strategies, in the fight against brain disorders such as autism and dyslexia in which sensory and multisensory processes are preferentially compromised.

[unreadable] DESCRIPTION (provided by applicant): Although there is growing evidence that developmental dyslexia is characterized by problems in basic sensory processes, there has been little work examining how information processing between the different sensory modalities is affected in this disorder. This is despite the fact that the development of reading and linguistic skills is an inherently cross-modal process, involving the integration of the visual and auditory components of the language representation. Based on the previous literature and our preliminary data, it is our hypothesis that dyslexics will indeed show a disorder in multisensory processing, which will manifest as an abnormally large window of time within which visual and auditory stimuli are bound into a unified percept. To test this hypothesis, and to examine the brain substrates that underlie these altered multisensory processes, we propose to conduct psychophysical and fMRI experiments. These experiments will use a multisensory temporal order judgment task in order to delineate the temporal window of multisensory integration in both dyslexic and normal reading subjects, as well as examining the differential patterns of brain activation in multisensory cortical regions during task performance. Together, the results of this study will serve to further our understanding of the neurophysiological bases of dyslexia. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The current application requests continuing support for a highly successful training program at Vanderbilt University that focuses on the fundamentals of neuroscience. The grant seeks support for fourteen predoctoral trainees, focusing on the first two years of Ph.D. training in the Neuroscience Graduate Program. This program is a joint venture between the School of Medicine and the College of Arts and Science, administered through the Vanderbilt Brain Institute. The goal of the training program is to provide a curriculum that assures that each student has a core knowledge in neuroscience, spanning a number of different levels from molecules and cells to higher order brain function. In addition to a core body of knowledge, we expect students to become scholars in the area of neuroscience that relates directly to their thesis research. Significant strengths include program leadership, world-class training faculty, excellent students and a highly collegial training environment. The program director is a well-known neuroscientist with excellent credentials and a stellar training career. The training program is characterized by an interdisciplinary curriculum combined with state-of-the-art research opportunities. Students choose between two focus areas (Molecular/Cellular Neuroscience or Integrative/Cognitive Neuroscience), with overlapping entry-level courses with advanced courses that are tailored to a specific interest. All trainees participate in ongoing seminars, alternating weekly between the Neuroscience Graduate Seminar, presented by a renowned visiting scholar, and the Neuroscience Research Forum, in which graduate students make scientific presentations. Research rotations during the first year allow students an opportunity to learn a variety of techniques and get to know a laboratory before making a decision about a thesis research home. The 54-member training faculty, representing fifteen departments across campus, have diverse, well-funded research programs. Areas of particular specialty include synaptic mechanisms, intracellular signal transduction, neural development, sensory systems, behavior, and genetics of brain diseases. Graduates have strong publication records and are pursuing scientific careers that will address the national needs for biomedical and behavioral research relevant to brain diseases and disorders.

DESCRIPTION (provided by applicant): This competing renewal application requests continued funding of the Meharry/Vanderbilt Alliance Training Program in Neuroscience, a linked predoctoral-postdoctoral program for research training with the goal to increase diversity in neuroscience research. Funds are also sought for a short term summer research program for underrepresented minorities, which serves as a pipeline for recruitment of strong candidates. The Meharry/Vanderbilt Alliance Training Program is uniquely equipped to make a difference in minority representation in neuroscience because it builds on a formal alliance between a historically black university and a research-intensive institution. Advantages include the close proximity of the two institutions, the long history of faculty interactions, outstanding program leadership, the excellent commitment and support by top administrators at both institutions, and documented evidence of outstanding trainees. Renewal of this training grant is crucial to continued success of the Alliance training program, which has been transforming at both institutions and has promoted the establishment of collaborative research programs and shared courses. The present grant seeks continued support for eight (8) predoctoral trainees at the alliance institutions, and also proposes a structured, mentored postdoctoral program (4 postdoctoral trainees), partnering with the NIMH Intramural Program to offer world-class faculty and facilities in translational neuroscience. Postdoctoral training focuses on the first two years post-graduation, a critical period of transition when a significant number of minority individuals change career paths or drop out. The predoctoral program is characterized by an interdisciplinary curriculum combined with state-of-the-art research opportunities, while the postdoctoral program offers an intense research experience, supplemented by didactic training as needed. The training faculty at Meharry and Vanderbilt have joined together to develop a new course, Neurobiology of Disease, which is required for predoctoral and postdoctoral trainees and serves as a focal point for deepening students'understanding of the neurobiology of diseases, from molecules to the disease pathology, and to extend that understanding to include the health disparities inherent in each disease. The combination of didactic training and research opportunities will prepare our graduates for future collaborations in research and research training along the basic-translational-clinical continuum.

DESCRIPTION (provided by applicant): As noted in the request for applications, a key aspect of heterogeneity in autism spectrum disorders (ASD) is a relatively high number of clinical interventions that are commonly provided but have limited or even no objective evidence to support implementation. Sensory integration deficit (SID) is a controversial but widely used diagnostic classification in ASD and sensory integration based treatment (SIT) is now routinely provided to children with autism spectrum disorder, but has an extremely limited evidence base. The purpose of this R34 proposal will be to complete developmental analyses in preparation for a relatively large randomized comparison trial examining the effects of commonly implemented sensory integration treatment techniques on communication development in ASD. A total of 40 participants with ASD will be randomly assigned to either a sensory integration (SIT) or pivotal response training (PRT) comparison condition. In addition, pre-and post intervention behavioral and neuro-imaging measures of multi-sensory processing will be gathered and analyzed to determine whether changes in multi-sensory processing are associated with SIT intervention. Two years of support are requested. PUBLIC HEALTH RELEVANCE: Children with autism spectrum disorder (ASD) display severe disruptions in communication and social interaction. There are many unproven treatments thought to improve the skills that are widely implemented. The purpose of this project will be to evaluate whether sensory integration treatment is associated with improvements in communication and social skills in children with ASD.

DESCRIPTION (provided by applicant): The long-term objective of the proposed work is to provide the first comprehensive view of how multisensory function changes across lifespan. Emerging literature suggests a surprisingly long development process leading up to the mature multisensory state, and intriguingly that multisensory function in later life may compensate to some degree for age-related loss of acuity within the individual senses. In addition to being the first project to detail these changes across lifespan, the work will provide important windows into individual variability in multisensory function, and how certain domains of multisensory function map onto other domains (e.g., spatial vs. temporal function). Finally, the work seeks to detail relationships between multisensory abilities and higher cognitive processes, given that cognition is grounded in both the integrity of the information contained within the incoming sensory streams and the integration between these streams. The experimental approach will employ a sophisticated battery of tasks to assess and relate multisensory and cognitive function. The proposed studies are oriented around two specific aims. The first is to characterize multisensory function in individuals ranging in age from 5 to 85. The second is to relate performance on our battery of multisensory tasks to performance on well-established cognitive tasks that index domains such as attention and working memory. Collectively these studies are predicated on the framework that multisensory function will change in systematic ways across lifespan, and that these changes will have important relationships to cognition. The significance of work lay in its potential to establish these relationships, which will have important implications for furtherig our understanding of the maturation and aging of perceptual and cognitive representations - issues of powerful

DESCRIPTION (provided by applicant): In the natural environment, the brain is often confronted with the daunting task of interpreting auditory signals that occur in the presence of noise, which can render important auditory events ambiguous and less salient. However, in naturalistic circumstances these auditory cues are typically accompanied by visual information, often from the same events. The presence of such coincident audiovisual cues can greatly amplify the salience of a stimulus of interest. However, although a number of studies have illustrated the behavioral and perceptual benefits of having multisensory (e.g., audiovisual) cues available, and a growing literature on the neural encoding processes that characterize multisensory interactions, very few studies have been able to link multisensory neural changes to their behavioral and perceptual correlates. To more firmly establish these links, we will train rhesus monkeys to detect or localize a target sound (signal), and ignore ongoing or simultaneously occurring non-target sounds (noise). The spatial and temporal relationships between the signal and noise will be varied, to evaluate their effects on how well the monkey detects or localizes the signal. Similar experiments will be performed with the addition of visual stimuli, whose location and/or timing will be varied such that it sometimes matches that of the signal, and sometimes that of the noise. This will allow us to assess the effects of non-auditory (visual) stimuli on auditory behavioral performance and allow us to evaluate brain mechanisms of multisensory integration. Neurophysiological recordings of neurons in the inferior and superior colliculi are expected to reveal their differential role in auditory and audiovisual detection and localization behaviors. The translational and clinical relevance of this work is very high for the hearing impaired and the elderly, in that auditory assistive devices often perform poorly in noisy environments. Greater knowledge of how the brain processes auditory signals within noise, and how visual information can enhance neural and behavior performance in complex environments, will be of great utility for the design of better technologies to deal with hearing loss and its profound impact on quality of life.

The National Science Foundation (NSF) Graduate Research Fellowship Program (GRFP) is a highly competitive, federal fellowship program. GRFP helps ensure the vitality and diversity of the scientific and engineering workforce of the United States. The program recognizes and supports outstanding graduate students who are pursuing research-based master's and doctoral degrees in science, technology, engineering, and mathematics (STEM) and in STEM education. The GRFP provides three years of financial support for the graduate education of individuals who have demonstrated their potential for significant research achievements in STEM and STEM education. This award supports the NSF Graduate Fellows pursuing graduate education at this GRFP institution.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

RESEARCH PLAN (OVERALL) ABSTRACT This U54 application seeks renewed funding for Vanderbilt University?s Intellectual and Developmental Disabilities Research Center (IDDRC), based in Vanderbilt?s Kennedy Center. Vanderbilt?s IDDRC includes the full range of basic, clinical, and intervention scientists necessary to fulfill the goals for the EKS NICHD IDDRC program of translational research that improves the lives of people with intellectual and developmental disabilities (IDD) and their families. Our IDDRC focuses on elucidating mechanisms and effective interventions for individuals with autism spectrum disorders, learning disabilities, genetic IDD syndromes, and acquired IDDs. Within each of these groups, IDDRC investigators discover underlying disease mechanisms, treatment targets, and aberrant developmental processes in model systems; assess cognitive, social, emotional, and neural phenotypes; and conduct innovative treatment and intervention studies. These activities are embodied in the U54 Research Project, Sensory and Multisensory Contributions to Autism, which meets the EKS NICHD Focus Theme #2: Outcome Measures for Interventions, and highlights an understudied but increasingly recognized characteristic of autism. Vanderbilt?s U54 IDDRC includes 46 investigators from 15 academic departments who lead 69 research projects; 14 are funded by the EKS NICHD. We propose five exceptional, non-duplicative IDDRC Cores to support these investigators and that are also integrated into each Specific Aim of the U54 Research Project. The Administrative Core A provides scientific direction, manages IDDRC governance committees and activities, and leads innovative training and educational programs. Clinical Translational Core B meets investigators? immediate needs for recruiting and phenotyping participants with IDDs, while also assisting with clinical trials, mining novel epidemiological data for IDD phenotyping, and building a new resource of IDD outcome measures. Translational Neuroimaging Core C assists investigators with neuroimaging and psychophysiology data acquisition, processing, and analyses; creates novel experimental paradigms, and proposes ?big data? approaches for large-scale investigations of IDD. Neuroscience Core D provides essential and inherently generative services in mouse neurobehavioral phenotyping, neurochemistry, molecular neurobiology and genomics, and scientific instrumentation, which designs, constructs, or repairs specialized research equipment. Biostatistics and Bioinformatics Core E improves research quality with expert biostatistical consultation and training on topics that are relevant to IDDs, and also develops unique bioinformatics databases of electronic medical record data from patients with IDDs that are linked to their DNA. IDDRC Cores are thus customized to meet the immediate needs of our investigators, and also to generate novel, forward-thinking technologies, tools, or resources that drive innovative discoveries aimed at understanding and ameliorating IDDs.

? DESCRIPTION (provided by applicant): The objective of the proposed project is to compare and contrast multisensory representation of peripersonal space (PPS) in two clinical groups: adults with autism spectrum disorder (ASD) and schizophrenia (SZ). The NIMH has stressed the importance of investigations that cross diagnostic categories and identify neural substrates of symptoms that are both shared and divergent across clinical groups. This project will follow this directive and extend it by focusing on basic sensory processes, which underlie more complex behavioral phenotypes and for which the neural bases are more completely understood. The project will assess the size and gradient of PPS representation in these two groups, within the hypothetical framework that shared social deficits exhibited in both groups may arise from divergent deficits in the multisensory representation of PPS. Individuals with ASD may show smaller representations of PPS and steeper gradients between PPS and extrapersonal space (EPS), reflecting a proximal focus of attention that leads to difficulty with reciprocal social interaction. In contrast, individuals with SZ are expected to show expanded PPS representation and shallower gradients between PPS and EPS, reflecting a distal or external focus that leads to problems distinguishing ownership. Both aberrant representations are predicted to relate to the specific social deficits observed in each group. We will also explor the malleability of these representations following a period of paired visual-tactile stimulation, which has been demonstrated to alter PPS representation in adults. While this exploratory aim is not designed to assess manipulating PPS representation as a treatment, and thus does not constitute an intervention study, we will assess the relationship between changes in PPS representation and social symptoms in each group as a preliminary step in determining whether there are links between these domains in ASD and SZ.

Neurodiversity is an emerging concept through which certain neurological differences - Autism, Attention Deficit Hyperactivity Disorder, Dyslexia, and others - are considered a natural part of human neurocognitive variation, associated not only with impairments but also with unique strengths. Indeed, many neurodiverse people have capabilities that are in high demand across many sectors, yet their potential remains vastly underutilized. This National Science Foundation Research Traineeship (NRT) award to Vanderbilt University will address this potential by training graduate students in a new interdisciplinary field of Neurodiversity Inspired Science and Engineering (NISE), which links human-technology frontiers (HTF) research and education across STEM disciplines through a cohesive focus on autism. The project anticipates providing a unique and comprehensive training opportunity for one hundred fifty (150) MS and PhD students, including forty-five (45) funded trainees, from computer science, mechanical engineering, data science, psychology, organizational science, and neuroscience. Students will engage in research that has as its goals: (i) understanding the unique capabilities associated with autism and learning to match these capabilities to 21st-century workforce needs, (ii) prototyping assistive technologies to enable employment and workplace success, and (iii) exploring organizational practices that help leverage the talents of autistic individuals and enhance organizational innovation.

The NISE NRT project seeks to train a new type of engineer and scientist, one who can devise innovations that support workforce engagement of individuals with autism and/or that are inspired by autistic capabilities. Building on the strengths of Vanderbilt's new Frist Center for Autism & Innovation, this NRT project will engage trainees in the development, deployment, and commercialization of HTF approaches and devices, providing broadly applicable skills in artificial intelligence, data science, robotics, virtual reality, and inclusive design. Collaboration with practitioners in clinical psychology, special education, and business, will ensure relevance of trainees' projects to the clinical, educational, and/or commercial domains. Trainees will participate in the Vanderbilt NSF I-Corps program as well as invention disclosure and patents. Research projects will also impact K-12 students and teachers in the communities where NRT trainees conduct their work. A central part of the program's plan to recruit, mentor, and advance women, underrepresented minorities, and persons with disabilities is the Fisk-Vanderbilt Masters-to-PhD Bridge Program, a national exemplar in STEM graduate diversity. Trainees will undertake, in addition to their regular graduate program requirements, a common core of three new NISE courses, summer school, workshops, and internships, culminating in a graduate certificate in NISE.

The NSF Research Traineeship (NRT) Program is designed to encourage the development and implementation of bold, new potentially transformative models for STEM graduate education training. The program is dedicated to effective training of STEM graduate students in high priority interdisciplinary or convergent research areas through comprehensive traineeship models that are innovative, evidence-based, and aligned with changing workforce and research needs.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.