Poster A12, Tuesday, August 20, 2019, 10:15 am – 12:00 pm, Restaurant Hall
Neuroimaging-genetics profiles in persistent developmental stuttering
Soo-Eun Chang1,2, Claudia Benito-Aragón3,4, Ho Ming Chow1,5, Jorge Sepulcre3,6;1Department of Psychiatry, University of Michigan, Ann Arbor, 2Cognitive Imaging Research Center, Department of Radiology, Michigan State University, East Lansing, 3Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 4University of Navarra School of Medicine, University of Navarra, Pamplona, Spain, 5Nemours/Alfred I. DuPont Hospital for Children, Wilmington, DE, USA, 6Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School
The neurobiological underpinnings of developmental stuttering, a speech disorder characterized by disrupted speech fluency, remain unclear. While recent studies have identified several genetic profiles associated with stuttering, how these specific genetic backgrounds impact brain structure and neuronal circuits and how they influence the emergence of stuttering remains unknown. Here we present two studies that aimed to identify the topological relationships between Allen Brain Atlas genetic expression profiles and structural/functional brain signatures in stuttering. In study 1, we conducted voxel-based morphometry (VBM) to examine brain structural changes associated with stuttering, and, in study 2, we identified the large-scale functional connectivity network that underlies stuttering using graph theory principles. In both studies, we performed spatial similarity analysis to examine whether the brain distinctive features of stuttering intersect with the protein-coding transcriptome data of the Allen Human Brain Atlas, using both a priori knowledge of previously reported stuttering genes in the literature, as well as data-driven approaches. Using these complementary strategies in Study 1 and 2, we were able to find that GNPTG – a gene involved in the lysosomal enzyme targeting pathways – was significantly co-localized with both the cortical volume changes and cortical network associated with stuttering. Moreover, an enrichment analysis demonstrated that the genes identified with the stuttering cortical network shared a significantly overrepresented biological functionality of Neurofilament Cytoskeleton Organization, mitochondrial adenosine triphosphate (ATP) synthesis and detoxification of reactive oxygen species (ROS). Gene ontology enrichment analysis identified with volumetric differences showed significant overrepresentation of genes involved in energy metabolism in mitochondria. These findings suggest that lysosomal dysfunction may be related to changes in specific metabolic pathways that impart deleterious effects on neurofilament organization in neuronal circuits of the stuttering speech network. While the connection between mitochondrial functions and stuttering remains to be elucidated, emerging evidence has shown that lysosome and mitochondria interact physically and functionally, and these interactions play an important role in modulating metabolic functions of the two organelles. In sum, based on parallel analyses of functional and structural MRI data associated with stuttering and gene expression maps, we report that stuttering-related functional connectivity networks and brain volume changes co-localize with gene expression of the lysosomal trafficking gene GNTPG. Mutations in this gene and other similar genes embedded within the same cortical topology of cerebral networks suggest that these mutations could modulate the function of these networks. Our findings point to the auditory-motor integration network as highly vulnerable to neuronal circuit dysfunctions associated with GNPTG mutations. These novel findings help bridge structural and functional neural network anomalies and gene mutation findings previously linked to stuttering.
Themes: Disorders: Developmental, Language Genetics
Method: Functional Imaging