It has been proposed that general abnormalities in structural and functional neuronal connectivity may underlie many of the triad of deficits observed in autism. A limited number of deficits at the neuronal level, widely expressed in multiple neurobehavioral systems could provide substantial explanatory power in autism. For example, abnormal temporal binding and weak central coherence may be related to alterations in brain functional and/or structural connectivity. Gamma band oscillatory activity, as measured using EEG and magnetoencephalography (MEG), has been associated with intrinsic GABAergic activity in animal and computational models of the neocortex and is thought to play an important role in binding and central coherence. We and others have published data demonstrating that gamma activity is abnormal in people with autism, possibly reflecting a cortical GABA dysfunction. Using a whole-head MEG system, we will assess patterns of auditory cortical synchronization with high precision in both time and frequency. As we are primarily interested in the development of new endophenotypes for autism, we will study parents of affected individuals as well as probands. Preliminary evidence from our laboratory indicates that a gamma- synchronization deficit may be familial. Forty families who have children with autism will be enrolled and the parents of the children will be assessed using MEG measures of gamma-band activity in auditory experiments. Their data will be compared to matched adults with no personal or family history of autism spectrum disorders their children. MEG measures of gamma power and phase-locking will be measured and associated with their structural underpinnings from magnetic resonance imaging (MRI) data and also with measures of the broad autism phrenotype.

Public Health Relevance

It has been proposed that general abnormalities in structural and functional neuronal connectivity may underlie many of the triad of deficits observed in autism. A limited number of deficits at the neuronal level, widely expressed in multiple neurobehavioral systems could provide substantial explanatory power in autism. For example, abnormal temporal binding and weak central coherence may be related to alterations in brain functional and/or structural connectivity. The long term goals of this application will be (1) to examine a putative electrophysiological underpinning of such problems, neuronal synchronization ability in the gamma band of the EEG and MEG, (2) to evaluate the familiality of evoked and induced gamma power and phase- locking factor in first degree relatives of people with autism, (3) in follow-up studies associate such deficits with GABAergic dysfunction and GABA receptor candidate genes and (4) evaluate pharmacological interventions that directly target GABA function. Gamma band oscillatory activity has been associated with intrinsic GABAergic activity in animal and computational models of the neocortex and is thought to play an important role in binding and central coherence

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH082820-04
Application #
8372405
Study Section
Child Psychopathology and Developmental Disabilities Study Section (CPDD)
Program Officer
Gilotty, Lisa
Project Start
2009-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2013
Total Cost
$254,470
Indirect Cost
$88,150
Name
University of Colorado Denver
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Rojas, Donald C; Wilson, Lisa B (2014) ?-band abnormalities as markers of autism spectrum disorders. Biomark Med 8:353-68
Rojas, Donald C; Singel, Debra; Steinmetz, Sarah et al. (2014) Decreased left perisylvian GABA concentration in children with autism and unaffected siblings. Neuroimage 86:28-34
Rojas, Donald C (2014) The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. J Neural Transm (Vienna) 121:891-905
Gadgil, Milind; Peterson, Eric; Tregellas, Jason et al. (2013) Differences in global and local level information processing in autism: an fMRI investigation. Psychiatry Res 213:115-21
Brown, Mark S; Singel, Debra; Hepburn, Susan et al. (2013) Increased glutamate concentration in the auditory cortex of persons with autism and first-degree relatives: a (1)H-MRS study. Autism Res 6:1-10
Wilson, Lisa B; Tregellas, Jason R; Slason, Erin et al. (2013) Phonological processing in first-degree relatives of individuals with autism: an fMRI study. Hum Brain Mapp 34:1447-63