MEG Imaging Techniques for Low-Functioning Pediatric Populations

Abstract: Whereas my previous training has focused on acquiring a strong technical foundation in neuroimaging methods, over time, my interests have evolved from a purely technical focus towards the application of neuroimaging to study brain dysfunction in pediatric patient populations. K01 training and research goals will provide me the skills and expertise needed to excel as an independent clinical imaging researcher in this area. To this end, I will obtain training in advanced state-of-the-art magnetoencephalography (MEG) analysis methods in order to study primary sensory activity in low-functioning children with autism spectrum disorder (ASD). Although neuroimaging studies, including MEG, have investigated sensory processing in ASD, these studies have primarily focused on higher-functioning individuals, as these patients are better able to tolerate neuroimaging exams. This leaves a significant portion of the ASD population unexamined and underserved (approximately 40% of the ASD population is low-functioning). Due to this research bias, relatively little is known directly about brain function in low-functioning individuals with ASD, or about the degree to which findings in higher-functioning ASD generalize to the entire ASD population. Although focusing on low- functioning ASD, K01 training and research is generalizable, specifically applicable to the examination of other low-functioning patient populations such as individuals with moderate to severe intellectual disability and cerebral palsy. It is towards these underserved and understudied low-functioning patient populations that I will focus my subsequent research. K01 work achieves significant advancements in several areas, with advancements moving me towards independence as a clinical imaging researcher. First, as part of my K01 research work, I will develop technical solutions to address primary obstacles to studying lower-functioning populations with MEG, namely the lack of anatomical information from structural MRI and the often considerable subject motion during a MEG exam. This technical work will serve as an enabling technology, allowing the inclusion of lower-functioning participants in MEG imaging studies. Second, significant time is spent on training activities that will provide me with a greater appreciation for the clinical and behavioral phenotypes exhibited in neurodevelopmental disorders as well as improving my understanding of the underlying neurobiology. To this end, under the guidance of Drs. Levy and Miller, I will participate in ongoing educational clinical activities already in place for training psychologists and other clinicians. I will spend 1 day per week in K01 Years 1 and 2 (2 days per month thereafter) performing clinical training and observing clinical and cognitive assessments at the Regional Autism Center’s young child clinic (seeing children under 6 years) and the Center for Autism Research’s school age clinic. These clinics see over 300 patients (~25-50% low-functioning) a year, offering ample opportunity to observe subjects with a wide variety of behavioral phenotypes and severity levels. This is in addition to attending case assessment meetings (as part of clinical observation), bi-monthly clinical team meetings and regular individual meetings with Drs. Levy and Miller. Training in the neurobiology of developmental disorders as well as the neurobiology of primary sensory processes will be achieved via coursework and one-on-one meetings with Dr. Contreras. Training, workshops, and coursework in the biology, presentation and clinical care of neurodevelopmental disorders will better enable me to anticipate and address the specific challenges in the study of these patient groups and to formulate and address biological questions central to these pediatric patient populations. Completion of this K01 encompasses the achievement of significant advancements in MEG acquisition and analysis. In particular, methods for atlas-based head modeling and motion compensation, developed in Aim 1, will permit accurate source localization of evoked primary sensory activity without the requirement of an MRI and in cases of large continuous motion. These methods will enable the study of primary sensory processes in low-functioning and non-compliant patient populations. Similarly, the real-time analysis system (Aim 3) represents a significant step forward in MEG acquisition in these patient groups, promising decreased scan time and thus decreased patient discomfort and fatigue. Technical advancements will be underpinned by additional training in advanced MEG physics and analysis provided Drs. Roberts, Mosher, and Dammers through one-on-one meetings and instruction. The utility and validity of these methods will be demonstrated through their application to low-functioning children and adolescents with ASD and via increases in success rate (evaluable data) and data quality. Investigation of atypical sensory activity, previously only reported in high-functioning ASD, will thus be enabled in a low-functioning ASD population, addressing the critical and presently unevaluated question of the generalizability of sensory abnormalities in ASD. K01 research will provide data in support of a future R01 which will likely focus on contrasting the sensory activity of low-functioning individuals with ASD to non-ASD neurodevelopmental disorders (e.g., 22q11.2 deletion syndrome, cerebral palsy) to identify the specific versus common pathways of sensory processing brain abnormalities in neurodevelopmental disorders.

Abstract: Whereas my previous training has focused on acquiring a strong technical foundation in neuroimaging methods, over time, my interests have evolved from a purely technical focus towards the application of neuroimaging to study brain dysfunction in pediatric patient populations. K01 training and research goals will provide me the skills and expertise needed to excel as an independent clinical imaging researcher in this area. To this end, I will obtain training in advanced state-of-the-art magnetoencephalography (MEG) analysis methods in order to study primary sensory activity in low-functioning children with autism spectrum disorder (ASD). Although neuroimaging studies, including MEG, have investigated sensory processing in ASD, these studies have primarily focused on higher-functioning individuals, as these patients are better able to tolerate neuroimaging exams. This leaves a significant portion of the ASD population unexamined and underserved (approximately 40% of the ASD population is low-functioning). Due to this research bias, relatively little is known directly about brain function in low-functioning individuals with ASD, or about the degree to which findings in higher-functioning ASD generalize to the entire ASD population. Although focusing on low- functioning ASD, K01 training and research is generalizable, specifically applicable to the examination of other low-functioning patient populations such as individuals with moderate to severe intellectual disability and cerebral palsy. It is towards these underserved and understudied low-functioning patient populations that I will focus my subsequent research. K01 work achieves significant advancements in several areas, with advancements moving me towards independence as a clinical imaging researcher. First, as part of my K01 research work, I will develop technical solutions to address primary obstacles to studying lower-functioning populations with MEG, namely the lack of anatomical information from structural MRI and the often considerable subject motion during a MEG exam. This technical work will serve as an enabling technology, allowing the inclusion of lower-functioning participants in MEG imaging studies. Second, significant time is spent on training activities that will provide me with a greater appreciation for the clinical and behavioral phenotypes exhibited in neurodevelopmental disorders as well as improving my understanding of the underlying neurobiology. To this end, under the guidance of Drs. Levy and Miller, I will participate in ongoing educational clinical activities already in place for training psychologists and other clinicians. I will spend 1 day per week in K01 Years 1 and 2 (2 days per month thereafter) performing clinical training and observing clinical and cognitive assessments at the Regional Autism Center’s young child clinic (seeing children under 6 years) and the Center for Autism Research’s school age clinic. These clinics see over 300 patients (~25-50% low-functioning) a year, offering ample opportunity to observe subjects with a wide variety of behavioral phenotypes and severity levels. This is in addition to attending case assessment meetings (as part of clinical observation), bi-monthly clinical team meetings and regular individual meetings with Drs. Levy and Miller. Training in the neurobiology of developmental disorders as well as the neurobiology of primary sensory processes will be achieved via coursework and one-on-one meetings with Dr. Contreras. Training, workshops, and coursework in the biology, presentation and clinical care of neurodevelopmental disorders will better enable me to anticipate and address the specific challenges in the study of these patient groups and to formulate and address biological questions central to these pediatric patient populations. Completion of this K01 encompasses the achievement of significant advancements in MEG acquisition and analysis. In particular, methods for atlas-based head modeling and motion compensation, developed in Aim 1, will permit accurate source localization of evoked primary sensory activity without the requirement of an MRI and in cases of large continuous motion. These methods will enable the study of primary sensory processes in low-functioning and non-compliant patient populations. Similarly, the real-time analysis system (Aim 3) represents a significant step forward in MEG acquisition in these patient groups, promising decreased scan time and thus decreased patient discomfort and fatigue. Technical advancements will be underpinned by additional training in advanced MEG physics and analysis provided Drs. Roberts, Mosher, and Dammers through one-on-one meetings and instruction. The utility and validity of these methods will be demonstrated through their application to low-functioning children and adolescents with ASD and via increases in success rate (evaluable data) and data quality. Investigation of atypical sensory activity, previously only reported in high-functioning ASD, will thus be enabled in a low-functioning ASD population, addressing the critical and presently unevaluated question of the generalizability of sensory abnormalities in ASD. K01 research will provide data in support of a future R01 which will likely focus on contrasting the sensory activity of low-functioning individuals with ASD to non-ASD neurodevelopmental disorders (e.g., 22q11.2 deletion syndrome, cerebral palsy) to identify the specific versus common pathways of sensory processing brain abnormalities in neurodevelopmental disorders.