Using EEG to Target GABA-a for the Treatment of Social Disability in Young Adults with Autism Spectrum Disorders

Background:  

Identification of biological targets could represent opportunities to intervene and  ameliorate core pathophysiology in ASD. Changes in resting and activated neuronal network oscillatory activity across various frequency bands are evident in ASD. To this end, NIMH Fast  Fail Trial in AS Network evaluated one compound, AZ7325 (a GABA_a2/a3partial agonist), by examining its target engagement, safety and tolerability, and preliminary efficacy indices. The GABA system  shows strong evidence of disruption in ASD and EEG has been investigated as translational biomarkers for examining putative decreased GABA signaling.  Most models of temporally organized oscillatory activity interpret the activity as the output of network interactions between interconnected glutamatergic pyramidal cells and GABAergic inhibitory interneurons (Bartos et al 2007), wherein GABAA signaling mediates phasic inhibitory control of excitatory pyramidal firing, the source of the EEG signal. 

Objectives:  

Our hypothesis is that administration of a selective GABA_a2/a3receptor partial agonist in an adult ASD sample is expected to result in specific EEG signatures of drug action consistent with selective target engagement. 

Methods:  

In Phase 1 (EEG Biomarker Validation): a battery of 4 EEG paradigms consisting of resting state, face perception, sensory perception, and frontal functioning were developed. Pilot data were  collected on 39 controls and 12 adults with ASD from 3 sites. All data were  collected using high density EEG under standardized settings. Each data file was artifact detected using Independent Component Analysis, and key features included the presence of posterior alpha activity in eyes closed and a N170 component to face stimuli. Analyses compared the ASD and Controls for identification of a biomarker that differentiated group functioning.  In Phase 2 (Double Blind Placebo Control Study), 24 adults with ASD from 3 sites were screened on the EEG paradigm and assessed for inclusion based on the identified biomarker. 

Results:  

Although there were few significant differences between ASD and Controls on a specific variable (e.g., non significant delta, theta, alpha ps>.10), a linear discriminant analysis consisting of 3 metrics (from resting state eyes closed and faces) were combined to provide a sensitivity of .8 and specificity of .7 for separation between groups. Using this combined marker as an inclusion criteria, we are currently completing Phase 2. Upon completion in Dec, the blind will be broken and analysis of baseline vs week 4 and week 6 EEG will be conducted for the active vs. placebo group. 

Conclusions:

Fast Fail AS is the first trial to develop a targeted EEG biomarker for use in investigating a GABA deficit in ASD. This study of AZD7325 may provide insight into the relevance of GABAergic medications in ASD and the role of EEG as a marker of treatment response.