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

Abstract

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.

The Relative Contribution of Cochlear Synaptopathy and Reduced Inhibition to Age-Related Hearing Impairment for People With Normal Audiograms

“…Therefore, the wave V/I amplitude ratio may not be a good indicator for central GABAergic inhibition, which may explain the lack of a correlation between this measure and the SCWT inhibition score. Thus, it remains possible that the SCWT inhibition score provides a measure of central GABAergic inhibition as indicated by the magnetic resonance spectroscopy studies on the relation between GABA levels and SCWT performance (e.g., Kühn et al, 2016; Mamiya et al, 2021; Piras et al, 2021; Sofuoglu et al, 2005).…”

“…We found an association between decreased inhibition, as assessed by the SCWT, and worse auditory temporal processing and SRTN (Figure 5A-C). Although the SCWT measures behavioral inhibition, GABA magnetic resonance spectroscopy studies have shown that performance of the SCWT is accompanied by GABA increases in the anterior cingulate cortex (Kühn et al, 2016), the caudate nucleus in the front-striatal circuitry (Mamiya et al, 2021) and the cerebellum (Piras et al, 2021). Furthermore, Sofuoglu et al (2005) showed that increasing synaptic GABA levels enhanced Stroop interference inhibition in a clinical study.…”

“…The Stroop test is widely and primarily used to assess the ability to inhibit cognitive interference that occurs when the processing of a specific stimulus feature impedes the simultaneous processing of a second stimulus feature, for example, when naming the ink color in which a color name is printed. Stroop inhibition, however, has also been associated with GABA levels in the brain (e.g., Kühn et al, 2016; Mamiya et al, 2021; Piras et al, 2021; Sofuoglu et al, 2005). Here, the Stroop test was used to directly assess the ability to inhibit cognitive interference as well as to indirectly assess GABA levels (Figure 1).…”

Learning to read Chinese promotes two cortico-subcortical pathways: The development of thalamo-occipital and fronto-striatal circuits

“…Fronto-striatal connectivity is a critical cortico-subcortical pathway involved in language and cognitive processing ( Gordon et al, 2021 ). The fronto-striatal pathway has been shown to be closely associated with a variety of cognitive abilities, including inhibitory control ( Ojha et al, 2022 ), working memory( Rodrigue et al, 2020 ; Hidalgo-Lopez and Pletzer, 2021 ), executive function ( Galandra et al, 2019 ), and cognitive flexibility ( Banaie Boroujeni, 2021 ); its impairment can lead to problems, such as attention-deficit/hyperactivity ( Cupertino et al, 2020 ; Mamiya et al, 2021 ) and reading disorder ( Hancock et al, 2017 ). From recent evidence, the thalamo-occipital and fronto-striatal connectivities seem to be two functional independent pathways.…”