Understanding neurotransmitter activity is fundamental to elucidating normal and diseased neuronal function, with glutamate (Glu) and ?-aminobutyric acid (GABA) being the brain's primary excitatory and inhibitory neurotransmitters. Such understanding is particularly critical in autism spectrum disorder (ASD), a set of neurodevelopment disorders characterized by persistent deficits in social communication and restricted, repetitive, and stereotyped patterns of behavior. Although varying in presentation and severity, ASD occurs in all ethnic and socioeconomic groups, has a lifelong duration, and affects an estimated 1 out of 68 children in the United States. Unfortunately, the etiologies of these disorders are not fully understood, and this technical development proposal to develop novel non-invasive imaging tools for studying ASD brain neurochemical biomarkers is in response to NIH PA 10-158 ?Research on Autism Spectrum Disorders?. The innovations to be evaluated under this project will help not only investigating ASD, but also other neuropsychiatric and neurodevelopmental disorders where advanced imaging techniques are needed. Despite the heterogeneity of ASD, patients may share final common biochemical pathways and potentially be responsive to similar treatments, and ASD is now hypothesized to result from an imbalance between excitatory and inhibitory neurotransmitters. Known as the ?E/I balance? theory, findings from both animal models and humans suggest ASD is characterized by hyper-excitability in critical brain regions due to increased Glu and/or decreased GABA. While in vivo evidence of such neurochemical imbalances is beginning to emerge through the use of J-edited 1H magnetic resonance spectroscopy (MEGA-PRESS being the current method of choice) robust in vivo measurements are time-consuming and problematic. Glu measurement is straightforward, but separation from closely related glutamine (Gln) is difficult. Furthermore, co-edited macromolecules (MMs) overlap the targeted GABA signal and account for 40-60% of the detected signal, leading investigators to refer to the resulting data as GABA+MMs or simply GABA+. MRS-detected MMs are also reported to exhibit regional variations, variability across normal subjects, and dependence on both age and pathology. Even for single-voxel studies, prior proposed MM-suppression techniques are not widely used, being either time-consuming or highly sensitive to B0 magnetic field variations. This proposal seeks to overcome these limitations via the systematic design, implementation, and testing of robust MM-suppressed J-edited single-voxel (Aims 1 and 2) and multi-voxel (Aim 3) sequences to measure these targeted neurochemicals, yielding time-efficient measurements from multiple brain regions. These new tools will be used to assess neurochemical imbalances in adolescent patients diagnosed with ASD (Aim 4).
The pathophysiology of autism spectrum disorder (ASD) is challenging to investigate in light of the characteristics of the patient population such as young age and limited cognitive abilities. We propose to develop novel methods for imaging key brain neurotransmitters, which will become routine research and clinical neuroimaging tools for evaluating normal and abnormal brain metabolism, identifying underlying brain structure-function relationships, and monitoring therapeutic interventions in both autism and other psychopathologies. The ultimate goal of this investigation is to provide new insights into the associated brain organizational and architectural disturbances observed in individuals with ASD.
| Hegarty 2nd, John P; Gu, Meng; Spielman, Daniel M et al. (2018) A proton MR spectroscopy study of the thalamus in twins with autism spectrum disorder. Prog Neuropsychopharmacol Biol Psychiatry 81:153-160 |
| Gu, Meng; Hurd, Ralph; Noeske, Ralph et al. (2018) GABA editing with macromolecule suppression using an improved MEGA-SPECIAL sequence. Magn Reson Med 79:41-47 |
