Sophie Molholm - US grants

DESCRIPTION (provided by applicant): Work on the neurophysiology of feature-based selective attention has almost exclusively been focused within a single sensory modality. Yet in the real world relevant objects are often specified in more than sense, and this likely results in selectively attending to inputs across multiple sensory systems. Clearly a full understanding of selective attention processes requires that the neurophysiology of selective attention be studies under conditions in which subjects are attending to related features across sensory systems. The primary aim of this proposal is to apply the high temporal resolution of electrophysiological recordings with the fine spatial resolution of functional magnetic resonance imaging, under identical task conditions, in order to characterize both the time course and neuroanatomical substrates of cross-sensory selective attention mechanisms in relation to the vast literature on uni-sensory selective attention. Importantly, this work will be extended to schizophrenia patients, to characterize the neurophysiology of selective attention deficits in this population. A variation of the selective attention paradigm of Hillyard (1973) will be used. Ultimately, findings on the neurophysiology of cross-sensory selective attention will provide a more complete picture of attentional processes, and add to the basis for understanding attentional dysfunction in patients with schizophrenia.

Functional neuroimaging studies in humans have established that many visual cortical areas are recruited during tactile tasks. Additional methodological approaches are necessary to characterize the role of such visual cortical activity during non-visual perception and the underlying neural mechanisms. With National Science Foundation funding, this research embodies a collaboration among Drs. Krishnankutty Sathian, John Foxe, and Charles Schroeder that brings different techniques to bear on the issue of multisensory form processing in extrastriate visual cortex. Functional magnetic resonance imaging (fMRI) in humans is being combined with event-related potential (ERP) studies in humans and neurophysiologic studies in macaque monkeys, using experimental designs common to the three methods. The high spatial resolution of fMRI and the high temporal resolution of ERP studies are mutually complementary and allow specification of the temporal profile of neural activity, as well as precise localization. Monkey studies entail a combination of field potential and action potential analyses that allow both direct comparison to human (ERP/fMRI) data and investigation of the cellular bases of ERP and fMRI effects. Specific Aim I investigates the recruitment of visual cortical activity by tactile form discriminations and Specific Aim II explores multisensory interactions between vision and touch, during tactile form perception. The combination of three complementary experimental approaches being brought to bear on a common set of questions, using a common set of tasks, is unique and promises to provide a much more complete picture of the relevant neural processes than any of the approaches in isolation. This tripartite approach allows the acquisition of convergent evidence on the specific brain mechanisms of multisensory interactions, which are increasingly recognized to be ubiquitous and essential for sensory processing as well as other aspects of cognition.

Among its broader impacts, this project exemplifies the value of bringing multiple experimental approaches to bear on a set of issues. The project is anticipated to lead eventually to improvement in assistive technology available to individuals with sensory deprivation of any kind. By establishing a long-term collaboration between the three principal investigators, students and post-doctoral trainees will be able to acquire expertise in more than one of the experimental approaches, interact with more than one mentor, and further, train explicitly in the emerging field of multisensory science, a field with few formal training opportunities.

[unreadable] DESCRIPTION (provided by applicant): An abundance of information enters our various sensory systems at any moment in time. Limited higher-order processing capacities require that only a sub-set of this information is processed beyond the basic sensory level. Selectively attending to locations, stimulus features, and whole objects are important ways in which we direct limited higher-order processing resources to task-relevant information. Thus far object-based attention has only been demonstrated within the visual sensory modality, showing that when attention is directed toward a single feature of an object (for example its color), the constituent task-irrelevant features of the object are also selected for preferential processing. However, objects tend to have characteristic features in multiple sensory modalities and thus when directing attention toward an object, it may well be advantageous to prime more than one sensory system to process features typical of that object. The goal of the proposed research is to test whether object-based attention is multisensory, such that attending to an object in one sensory modality results in the preferential processing of its characteristic features in unattended sensory modalities. Using a variation of the classical selective attention paradigm of Hillyard, high-density scalp recorded event-related potentials will be used to assess the presence of selective attention effects. Auditory, visual, and auditory- visual objects will be presented to subjects, and in different blocks they will be instructed to perform a task on the auditory or the visual objects. The presence of selective attention effects for attended objects presented in task-irrelevant sensory modalities (e.g., for the auditory element of the attended object during visual attention blocks) would indicate that selectively attending to an object results in the preferential processing of its constituent features even when they are presented in ignored sensory modalities. Understanding how these multisensory attentional processes work in healthy subjects will ultimately allow us to consider how they may breakdown in clinical groups such as persons with schizophrenia and autism. Attentional deficits are considered a hallmark of schizophrenia; and a popular theory of autism at present is that it is a "sensory integration" disorder, though little empirical data has been collected toward testing this theory. Project Narrative: Year one: Experiments 1a and 1b are programmed and ready to be run on the same set of subjects. The first step then will be to recruit subjects, and begin data collection for Experiments 1a and 1b. Within the course of the year the full dataset will be collected and fully processed. This includes the statistical analysis of the data and source modeling of the selective attention effects across the different conditions. These data will then be presented at scientific meetings such as CNS and the international multisensory research forum (IMRF), and I will begin to work on reports for submission to peer review journals. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Atypical integration of multisensory inputs has been suggested as a major component of autism, with some clinical and behavior-based empirical support for this view. Where and when in the neural processing stream these sensory integration deficits occur is as yet unknown, and gaining an understanding of this will be essential in defining the neuropathology of autism. In fact, there is precious little understanding of the basic development of healthy sensory integration mechanisms in typically developing children, although recent work in animal models is beginning to shed some light. Under this project, we will use established electrophysiological metrics of multisensory integration that we have developed in our laboratory in healthy adults, to test the hypothesis that multisensory integration is impaired in autism. The high-density electrical recordings of neural activity that we record will provide a precise measure of when in the information processing stream sensory integration differs from typically developing matched controls, as well as a good model of the underlying brain processes that are affected. We expect that there are profound developmental effects on how multisensory inputs are treated and we will therefore also characterize the normal developmental trajectory of multisensory integration in typically developing children, using a cross-sectional approach. Specific hypotheses about when and where multisensory processes will be affected in autism are made based on the thesis that there is impoverished connectivity between distant cortical regions in this population, and our predictions are predicated on a rudimentary three-stage model of multisensory integration that we have developed in light of the extant literature. The data acquired under this project will provide a strong empirical test of deficits in multisensory integration processes in autism. Understanding how multisensory integration develops and changes over childhood will significantly inform models of multisensory integration, and provide an initial benchmark against which predictions about possible disordered multisensory integration in a host of developmental disorders can be made.

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ ABSTRACT DESCRIPTION: See instructions. State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. Autism Spectrum Disorder (ASD) is a common, often devastating neuropsychiatric condition with largely unknown pathophysiology. Although ASD has a multifactorial etiology, it encompasses a large genetic component. The investigators in this proposal aim to continue and enhance our collaborative effort that has produced significant advances in our understanding of ASD over the last four years and generated highly successful, open data and biomaterials resources for the research community, the NIMH Genetics Initiative and the Autism Genetic Resource Exchange (AGRE). Our Network has met or exceeded our original aims. We have built patient resources for research, identified rare and common ASD susceptibility alleles, defined models of ASD genetic susceptibility, provided evidence for convergent pathophysiology, and led development of animal and cell culture models. Here we propose to take a major new direction, filling a significant gap in ASD research, by recruiting underserved subjects of self-reported African ancestry (African-American; AA), an important population that has not previously been well-represented in ASD genetics research. Our Network involves six research sites and the AGRE DCC, collaborating in a systematic, comprehensive investigation of ASD genetics in order to identify rare mutations, chromosomal abnormalities, and common variation contributing to ASD susceptibility in the AA population. Specifically, we will enrich existing resources by recruiting at least 600 AA probands and additional family members. Our recruitment plan includes an embedded health disparities project that will evaluate access to care for AAs with ASD and clarify factors influencing participation of AA individuals in genetic research. We will employ novel methods to define the ancestral origin of specific chromosomal segments and ascertain the background on which susceptibility alleles occur. We will perform follow up GWA on ASD-related endophenotypes or co-variates, such as language delay, sex and head circumference. In parallel, we will conduct whole exome sequencing (WES) and analysis of copy number variation (CNV) using 2.5M SNP arrays yielding high resolution molecular karyotypes and providing a resource on genome-wide CNV and coding sequence variation (SNV) in ASD. Gene expression profiling and network analysis will be used to prioritize variants. Genetic risk factors identified in the mostly European samples will be tested for association in the AA sample to determine whether these cohorts share the same genetic risk factors, using a sample size providing power to replicate previous associations and to identify rare, recurrent CNV and SNV. The observation of new forms or different population frequencies of ASD-related variation in this sample as well as the sharing of most CNV and SNV with other cohorts are both outcomes that will have great significance for future studies and clinical care. As has been our practice, our Network will make all phenotypic and genotype data accessible via the internet on a rolling basis, further enhancing the value of this resource to the community.

  PROJECT SUMMARY (OVERALL) The overarching purpose of the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (RFK IDDRC) is to improve the lives of children with intellectual and developmental disabilities (IDD). Fifty years of distinguished progress in basic, translational and clinical research as one of NICHD's flagship IDDRCs, coupled with important recent faculty recruitments and an historic merger between the Albert Einstein College of Medicine and its University-Affiliated Hospital, Montefiore Medical Center, offer a solid platform for continuing excellence in our commitment to IDD research. The Center's 4 highly integrated and complemen- tary scientific Cores consist of: 1) our clinical translational core known as the Human Clinical Phenotyping (Core B, HCP), which serves to facilitate both access to and characterization of participants for IDD relevant research; 2) a Neurogenomics facility (Core C, NGEN) that provides cutting edge epigenetic and genomic processing and analyses on both human and animal tissues; 3) a Neural Cell Engineering and Imaging facility (Core D, NCEI) that provides state-of-the-art approaches to brain cell manipulation and visual-ization; and 4) an Animal Phenotyping facility (Core E, AP) for evaluation of animal behavior, metabolism, imaging and brain function in a manner with strong parallels to approaches taken in patients accessed through HCP. Each of our scientific Cores is carefully overseen and monitored by the Administrative Core (Core A, ADM), which also serves as the head ganglion of the entire IDDRC in its outreach programs to the Einstein/ Montefiore community as well as nationally. Each scientific Core is tightly connected to our selected Research Project which brings together a multidisciplinary team of investigators focused on intellectual disability in 22q11.2 Deletion Syndrome (22q11.2DS). A central function of the RFK IDDRC is to promote the substantive links between Einstein research laboratories and clinics at the Children's Evaluation and Rehabilitation Center (CERC) Children's and the Hospital at Montefiore (CHAM). Together, this set of Cores and our research project form a dynamic network of IDD-focused programs and practices that interlink 19 different academic departments and 20-plus IDD-relevant clinics at Einstein and Montefiore. The latter include 22q11.2DS, Rett and Williams syndromes, tuberous sclerosis, neurofibromatosis, West syndrome and infantile spasms, autism spectrum disorders, and a wide range of lysosomal diseases. New initiatives being set in motion involve outcome assessments of premature birth in terms of IDD and newborn screening (NBS) and critical genotype/ phenotype issues in conditions of high relevance to such NBS programs in New York State (Krabbe disease and adrenoleukodystrophy). Strong outreach programs driven by our ADM core help spread the word about IDD research. Such efforts over the past 5 years have positioned the RFK IDDRC in a substantive leadership role in coupling research and clinical strategic goals across the newly merged Einstein-Montefiore community, and will play an essential role in promotion of new clinical-research partnerships going forward.

This application is for a new T32 institutional training program to support postdoctoral research in intellectual and developmental disabilities (IDDs). The Rose F. Kennedy Center and its program of IDD research has for 50 years been in the forefront of discoveries in brain development, function and disease. Today, we are in an era of unprecedented discovery of new genes and gene variants, as well as environmental and related conditions, linked to IDD. At the same time, we are armed with remarkable advances in modern research tools in neuroscience, genetics and in cell and molecular biology. Our goal here is to create a vibrant new training program that successfully brings together talented postdoctoral fellows working with world-class investigators and their laboratories to develop the next generation of highly motivated and successful IDD-focused research scientists. The four broad objectives of this program are (1) to provide in-depth research experiences and didactic training in biomedical science for highly talented postdoctoral fellows in a manner that shapes their lifetime career objectives and at the same time fosters discovery and advancement of our understanding of, and ability to treat, specific types of IDDs; (2) to build effective cross-discipline communication between basic research laboratories and IDD-focused clinics, sensitizing our postdoctoral trainees to the perspective of IDD-focused clinicians and vice versa; (3) to extend this network of cooperation between trainees and their laboratories, and clinicians and their clinics, to encompass whenever possible the parents/care providers and IDD-affected patients; and (4) to provide career guidance and professional development to our trainees, with this effort coupled to our goal to recruit and train members of underrepresented minority groups. To accomplish these important goals, we have assem- bled a team of 36 highly talented primary trainers selected from our 100-member Rose F. Kennedy IDDRC membership. These individuals come from 15 basic science and clinical departments and span a host of research approaches to IDD ? from human investigations including iPSC studies, to mouse, fish, fly and worm models of IDDs. In addition, we have developed a structured training program designed to broaden the trainees IDD-focus well beyond the immediate lab experience. We have also established a plan of mentoring committees to guide our trainees along with evaluation processes allowing us to continually monitor and modify our program to ensure we are on track to our stated goals. Finally, we have engaged our clinical partners working with patients with IDDs and established a strong role for them in the training program. This program brings our institution?s considerable depth, rigorous scientific approach, and tradition of innovation to bear on the important study of the cause, treatment and prevention of intellectual disability.

PROJECT SUMMARY/ABSTRACT (OVERALL) The overarching purpose of the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (RFK IDDRC) is to improve the lives of children with intellectual and developmental disabilities (IDDs). Fifty- plus years of distinguished progress in basic, translational and clinical research as one of NICHD?s flagship IDDRCs, coupled with important recent faculty recruitments and an historic merger between the Albert Einstein College of Medicine and its University-Affiliated Hospital, Montefiore Medical Center, offer a solid platform for continuing excellence in our commitment to IDD research. The Center?s 4 highly integrated scientific Cores consist of: 1) our clinical translational core known as the Human Clinical Phenotyping (Core B, HCP), which serves to facilitate both access to and characterization of participants for IDD relevant research; 2) a Neurogenomics facility (Core C, NGEN) that provides cutting edge epigenetic and genomic processing and analyses on both human and animal tissues; 3) a Neural Cell Engineering and Imaging facility (Core D, NCEI) that provides state-of-the-art approaches to brain cell manipulation and visualization; and 4) an Animal Phenotyping facility (Core E, AP) for evaluation of animal behavior, metabolism and imaging in a manner with strong parallels to approaches taken in patients accessed through HCP. Each of our scientific Cores is carefully overseen and monitored by the Administrative Core (Core A, ADM), which also serves as the head ganglion of the entire IDDRC in its substantial outreach programs to Einstein/Montefiore, the Bronx community as well as nationally. Each scientific Core has an essential connection to our signature Research Project which brings together a multidisciplinary team of investigators focused on mechanisms of IDD in children with mutations in the transcriptional regulator lysine demethylase 5c gene, KDM5C. A central function of the RFK IDDRC is to promote the substantive links between Einstein research laboratories and clinics at the Children's Evaluation and Rehabilitation Center (CERC) and the Children?s Hospital At Montefiore (CHAM). Together, our Cores and research project form a dynamic network ? a community ? of IDD-focused programs and practices that interlink 18 different academic departments, >100 IDDRC members and 20-plus IDD-relevant clinics at Einstein and Montefiore. The latter include 22q11.2DS, Rett and Williams syndromes, tuberous sclerosis, neurofibromatosis, West syndrome and infantile spasms, autism spectrum disorders, and a wide range of neurometabolic disorders. New initiatives moving forward at this time include our unique precision medicine/community outreach program we call Operation IDD Gene Team, our goal to fortify ties with our Einstein clinical partner (CERC and its affiliated UCEDD and LEND programs) under the umbrella of the Rose F. Kennedy Center and a heightened focus on training through our newly established T32 for IDD postdoctoral fellows.

PROJECT SUMMARY/ABSTRACT (CORE B: HUMAN CLINICAL PHENOTYPING CORE ? HCP) The objective of the Human Clinical Phenotyping (HCP) Core is to promote excellence in human phenotyping, with a central mission to facilitate research on intellectual and developmental disabilities (IDDs) by a diverse interdisciplinary team of investigators across the Einstein/Montefiore campuses. To this end the HCP provides recruitment and sophisticated human phenotyping services for IDDRC investigators (Aim 1). The HCP implements an extensive program of community outreach and recruitment to increase diversity in research on intellectual and developmental disabilities and expose local children to the wonders of science and research (Aim 2). The HCP maintains an extensive and actively growing database of potential research participants that, in addition to including participant characteristics and clinical and cognitive assessment results, records the presence of neuroimaging data and genetics samples for that participant (Aim 3). This database serves to reduce recruitment and phenotyping costs for investigators, ease the burden of participation for families, and minimize redundant testing efforts across different research groups. De-identified participant information is readily available to IDDRC investigators through this centralized database. The HCP also provides IDDRC members access to state-of-the-art human neuroimaging resources (Aim 4) and engages in the development of next-generation phenotyping tools (Aim 5). The HCP actively disseminates research findings and information about ongoing research projects to the local community, and information about HCP Core resources and opportunities for collaboration to the Einstein/Montefiore researchers and clinicians (Aim 6). Since its inauguration 10-years ago, the HCP has become an integral part of human IDD work at Einstein/Montefiore. For example, it is essential to Einstein?s role in an ?Autism Centers of Excellence Network? project on the genetics of autism in individuals of African descent (MH100027), and it has been vital to a number of clinical-research partnerships including a basic neuroscience-HCP collaboration that led to the identification of a novel IDD syndrome (ANKS1B haploinsufficiency syndrome). Under the P50 the HCP will continue to support these interwoven aims to promote the mission of the RFK IDDRC to advance diagnosis, prevention, and treatment of children with IDDs. In addition, it will serve the proposed IDDRC signature Research Project by generating a research database of individuals affected by KDM5C mutations (Aim 7). Through these aims the HCP will maintain its role as the central hub for a variety of Center investigators for whom comprehensive human phenotyping is key to understanding the implications of their work.