It is thought that impairments in the main inhibitory neurotransmitter GABA underlie Autism, at least to some degree. Children with Autism often show abnormal touch processing as well as abnormal motor control, which have a large impact on social interactions and quality of life. GABA plays an important role in the regulation of both tactile and motor processing and it is possible that such symptoms are driven by impaired GABAergic function. However, it remains unclear how cortical dysfunction leads to behavioral dysfunction and how different GABAergic processes contribute to behavioral abnormalities. It has become possible to measure tactile sensitivity objectively using psychophysics, and we developed tasks that are based on invasive studies of sensory function, and can be linked to GABAA and GABABergic mechanisms. Recently we have shown impaired tactile sensitivity in children with Autism, showing poor amplitude discrimination (GABAA) and detection threshold (GABAB), and we showed reduced GABA levels using Magnetic Resonance Spectroscopy. However, a direct connection between specific GABAergic mechanisms and behavior has not yet been shown. It is possible to directly test GABAA and GABAB-ergic mechanisms using peripheral and transcranial magnetic stimulation (TMS) methods as has been shown by pharmacological studies. Applying these non-invasive stimulation methods will form the training portion of this application. The overall goal of this grant is to investigate specific inhibitory mechanisms in SM1 in children with ASD and their relation to sensory behavior. Using a multimodal non-invasive approach, we aim to test whether different GABAergic mechanisms are indeed impaired in children with Autism, whether these are linked to sensorimotor behavior and symptom severity, and how these relate to cortical GABA levels. We hypothesize that behavioral tasks and brain stimulation protocols that utilize inhibition will be impaired in childrn with ASD, and that performance that performances between conditions that probe the same GABAergic mechanisms (GABAA (e.g. amplitude discrimination and TMS measuring short-interval cortical inhibition) or GABAB (e.g. detection thresholds and TMS measuring long-interval cortical inhibition) are associated. A better understanding of the role of GABAergic dysfunction in autism may allow for the development of specific therapies that can alleviate the symptoms and improve quality of life.

Public Health Relevance

Children with Autism often suffer from impaired processing of touch, or abnormal control of their movements. It is thought that a deficit in the functioning of te main inhibitory neurotransmitter GABA underlies these sensorimotor impairments, but the relationship between inhibitory dysfunction (what happens in the brain) and behavioral impairments (the behavioral that is ultimately shown) is not well understood, so we will investigate this link using multimodal and noninvasive methodologies. Understanding the role of GABAergic dysfunction may lead to the development of therapies or interventions to alleviate symptoms in these children and significantly improve quality of life.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Career Transition Award (K99)
Project #
1K99MH107719-01A1
Application #
9108119
Study Section
Special Emphasis Panel (ZMH1-ERB-S (01))
Program Officer
Sarampote, Christopher S
Project Start
2016-07-01
Project End
2018-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$82,734
Indirect Cost
$6,128
Name
Johns Hopkins University
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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Mikkelsen, Mark; Wodka, Ericka L; Mostofsky, Stewart H et al. (2018) Autism spectrum disorder in the scope of tactile processing. Dev Cogn Neurosci 29:140-150
Hermans, Lize; Leunissen, Inge; Pauwels, Lisa et al. (2018) Brain GABA Levels Are Associated with Inhibitory Control Deficits in Older Adults. J Neurosci 38:7844-7851
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Porges, Eric C; Woods, Adam J; Edden, Richard A E et al. (2017) Frontal Gamma-Aminobutyric Acid Concentrations Are Associated With Cognitive Performance in Older Adults. Biol Psychiatry Cogn Neurosci Neuroimaging 2:38-44
Saleh, Muhammad G; Oeltzschner, Georg; Chan, Kimberly L et al. (2016) Simultaneous edited MRS of GABA and glutathione. Neuroimage 142:576-582
Edden, Richard A E; Oeltzschner, Georg; Harris, Ashley D et al. (2016) Prospective frequency correction for macromolecule-suppressed GABA editing at 3T. J Magn Reson Imaging 44:1474-1482
Oeltzschner, Georg; Puts, Nicolaas A J; Chan, Kimberly L et al. (2016) Dual-volume excitation and parallel reconstruction for J-difference-edited MR spectroscopy. Magn Reson Med :

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