Task-related excitatory/inhibitory ratios in the fronto-striatal circuitry predict attention control deficits in attention-deficit/hyperactivity disorder

Reduced GABA concentrations at rest in the fronto-striatal circuitry are repeatedly implicated in cognitive symptoms of ADHD. However, recent evidence has suggested that GABA and its precursor, glutamate, are capable of undergoing dynamic modifications in response to environments. Yet, it remains unclear how the dynamics between glutamate and GABA may change when people are exerting their control of attention, and whether they would predict attention control deficits in ADHD. To study this question, we used MR spectroscopy to quantify GABA and glutamate+glutamine (Glx) concentrations in the anterior cingulate cortex (ACC) and the caudate nucleus in the fronto-striatal circuitry while subjects were performing attention control tasks. We studied 19 adults with ADHD (31-51 years) and 16 adults without ADHD (28-54). We found GABA and Glx concentrations during the tasks increased in both subjects with or without ADHD, but the extent of increases was significantly reduced in subjects with ADHD. Notably, E/I ratios (Glx/GABA) also increased and significantly predicted error rates while subjects with or without ADHD performed the Stroop and Flanker tasks. Critically, regression models including E/I ratios, GABA concentrations, and the ADHD diagnosis significantly predicted task performance in these tasks. Furthermore, clear interactions among these factors predicted the impaired attention control in the Flanker task in subjects with ADHD. These findings demonstrate for the first time that E/I ratios in the ACC and the caudate nucleus increased when people exerted their control of attention, and suggest that reduced GABA contribution to E/I ratio in these two brain regions may account for cognitive deficits in ADHD.