This Mentored Patient-Oriented Research Career Development Award will develop the candidate into an independent physician-scientist with expertise in neuroimaging investigations of biomarkers of social cognition that may predict treatment response and facilitate identification of novel therapeutic targets and approaches for individuals with autism spectrum disorders (ASD). ASD is a neurodevelopmental disorder that is increasing in prevalence, and is characterized by deficits in social communication and interaction across multiple contexts, and restricted, repetitive patterns of behavior, interests, or activities. The majority of individuals with ASD have poor outcomes in the area of social functioning; however, there are no medical treatments available that target the core social communication deficits. The goal of the proposed research is to understand the neurobiological role of an imbalance in excitatory (glutamate) and inhibitory (gamma-aminobutyric acid, GABA) neurotransmission in the social cognition deficits in ASD, and to develop proton magnetic resonance spectroscopy as a measurement of target engagement to measure the ability of a medication, gabapentin, to increase cortical GABA levels. Spectrally-edited proton magnetic resonance spectroscopy (1H-MRS) provides an ideal method for measuring cortical GABA levels. All proposed studies will be in 70 adolescents (male and female) with ASD (age 13 to 17 years).
Specific Aim 1 : To measure correlations of 1H-MRS GABA levels in the anterior cingulate cortex (ACC) and occipital cortex (OC) with clinical measures of social cognition at baseline.
Specific Aim 2 : To measure the effect of an initial one time dose of gabapentin on 1H-MRS GABA levels in the ACC and OC. The application also outlines a detailed training plan involving didactic coursework, seminars, scientific conferences, and mentored experiences to provide the candidate with training in: (1) advanced neuroimaging techniques to study the neural correlates of social cognition in ASD; (2) clinical trials research methodology with a goal of integrating neuroimaging wraparound studies into the methods; and (3) advanced biostatistics and data analysis of complex neuroimaging datasets and clinical trials data. This NIMH K23 is the bridge (i.e. pathway for training and mentorship) for this early stage investigator to develop into an independently-funded researcher with the expertise to conduct neuroimaging studies of social cognition in ASD and contribute to the development and understanding of novel therapeutic approaches in these disorders.
Autism spectrum disorders (ASD) have a significant social, economic, and public health impact, and are increasing in prevalence, with recent estimates that 1 in 50 children are affected. ASD is characterized by difficulties with social communication and social functioning, but no medical treatments are available to treat the social communication problems. Evidence is emerging that glutamate and GABA, neurotransmitters in the brain, are directly associated with social communication difficulties: we will use brain imaging to investigate glutamate and GABA in ASD; and investigate the use of MRI technology to measure the effect of a medication on brain GABA levels in adolescents with ASD.
