Autism Spectrum Disorders (ASD) has complex and varying etiologies. A lack of understanding regarding the underlying molecular and cellular mechanisms is a key barrier in finding effective treatments. Single-gene disorders that have a high prevalence of ASD provide unique opportunities to investigate the underlying biology and test treatments for autism. Tuberous Sclerosis Complex (TSC) is a genetic disorder in which approximately 50% of individuals are also affected with ASD. Importantly, TSC can be diagnosed before or at the time of birth, and thus infants with TSC allow us to observe prospectively the natural history of ASD and develop better tools for early detection of autism. On a molecular level, TSC disease manifestations result from the aberrant hyperactivity of mTOR that is caused by mutation in one of two TSC genes. Pharmacologic mTOR inhibition to correct the cellular defects in TSC is no longer a hope for the future, but rather an exciting reality with proven efficacy against various TSC disease manifestations. To determine the potential benefit these agents may have in treating or preventing ASD, it is imperative to identify early markers of autism in infants with TSC, so as to not put young children who will not develop ASD at unnecessary risk. Accumulating clinical and basic science evidence suggests that aberrant white matter connectivity represents a rational candidate as a biomarker in TSC. TSC mouse models demonstrate defects in the specification, guidance, and myelination of axons. More importantly, several groups have reported abnormalities in the normal-appearing white matter of TSC patients that can be identified by MR imaging, and loss of white matter microstructural integrity is associated with neurological and cognitive deficits. Furthermore, there is preliminary data indicating that white matter integrity can be improved by treatment with mTOR inhibitors in both animal models and in TSC patients. Taken together, these findings lead to the hypothesis that longitudinal assessment of white matter integrity and neural connectivity in TSC infants, through advanced MRI and EEG analysis, can be used as an early biomarker of subsequent ASD in this genetic disease. This proposal aims to establish a consortium of five Children's Hospitals that are geographically-distributed throughout the US to recruit TSC patients in the first year of life to test this hypothesis. State of the art imaging with 3Tesla MR scanners, advanced EEG technology, validated neurodevelopmental assessment tools, genetic analysis, and standardized clinical measures through age 36 months will be utilized. The clinical consortium will be supported by a centralized Data Coordinating Center with experience in another rare disease (neurofibro- matosis). Collaboration with Leadership Education in Neurodevelopmental and Related Disabilities (LEND) programs at each center will provide additional interdisciplinary research training and education expertise in ASD and TSC. As a result of the research outlined in this proposal, better understanding of brain connectivity and it relationship to ASD in TSC will pave the way for new interventions for this and related causes of autism.
Studying infants with Tuberous Sclerosis Complex (TSC), a genetic disorder with a high prevalence of ASD that can be diagnosed before or at the time of birth, allows us to develop better tools for early detection of autism. We will investigate whether longitudinal assessment of brain connectivity using MRI and EEG in children with TSC can identify an early biomarker of subsequent ASD in this genetic disease. This will result in better understanding of brain connectivity and its relationship to ASD in TSC and will pave the way for new interventions for this and related causes of autism.
|de Vries, Petrus J; Wilde, Lucy; de Vries, Magdalena C et al. (2018) A clinical update on tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Am J Med Genet C Semin Med Genet 178:309-320
|Modi, Meera E; Sahin, Mustafa (2018) A unified circuit for social behavior. Neurobiol Learn Mem :
|Nariai, Hiroki; Wu, Joyce Y; Bernardo, Danilo et al. (2018) Interrater reliability in visual identification of interictal high-frequency oscillations on electrocorticography and scalp EEG. Epilepsia Open 3:127-132
|Marami, Bahram; Scherrer, Benoit; Khan, Shadab et al. (2018) Motion-robust diffusion compartment imaging using simultaneous multi-slice acquisition. Magn Reson Med :
|Modi, Meera E; Sahin, Mustafa (2018) The Way Forward for Mechanism-Based Therapeutics in Genetically Defined Neurodevelopmental Disorders. Clin Pharmacol Ther 104:603-606
|Rensonnet, Gaëtan; Scherrer, Benoît; Warfield, Simon K et al. (2018) Assessing the validity of the approximation of diffusion-weighted-MRI signals from crossing fascicles by sums of signals from single fascicles. Magn Reson Med 79:2332-2345
|Hussain, Shaun A; Mathern, Gary W; Hung, Phoebe et al. (2017) Intraoperative fast ripples independently predict postsurgical epilepsy outcome: Comparison with other electrocorticographic phenomena. Epilepsy Res 135:79-86
|Capal, Jamie K; Bernardino-Cuesta, Beatriz; Horn, Paul S et al. (2017) Influence of seizures on early development in tuberous sclerosis complex. Epilepsy Behav 70:245-252
|Srivastava, Siddharth; Sahin, Mustafa (2017) Autism spectrum disorder and epileptic encephalopathy: common causes, many questions. J Neurodev Disord 9:23
|Eaton-Rosen, Zach; Scherrer, Benoit; Melbourne, Andrew et al. (2017) Investigating the maturation of microstructure and radial orientation in the preterm human cortex with diffusion MRI. Neuroimage 162:65-72
Showing the most recent 10 out of 49 publications