Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that impairs the control of attention and behavioral inhibition in affected individuals. Recent genome-wide association findings have revealed an association between glutamate and GABA gene sets and ADHD symptoms. Consistently, people with ADHD show altered glutamate and GABA content in the brain circuitry that is important for attention control function. Yet, it remains unknown how glutamate and GABA content in the attention control circuitry change when people are controlling their attention, and whether these changes can predict impaired attention control in people with ADHD. To study these questions, we recruited 18 adults with ADHD (31–51 years) and 16 adults without ADHD (28–54 years). We studied glutamate + glutamine (Glx) and GABA content in the fronto-striatal circuitry while participants performed attention control tasks. We found that Glx and GABA concentrations at rest did not differ between participants with ADHD or without ADHD. However, while participants were performing the attention control tasks, participants with ADHD showed smaller Glx and GABA increases than participants without ADHD. Notably, smaller GABA increases in participants with ADHD significantly predicted their poor task performance. Together, these findings provide the first demonstration showing that attention control deficits in people with ADHD may be related to insufficient responses of the GABAergic system in the fronto-striatal circuitry.

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.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that has become increasingly prevalent worldwide. Its core symptoms, including difficulties regulating attention, activity level, and impulses, appear in early childhood and can persist throughout the lifespan. Current pharmacological options targeting catecholamine neurotransmissions have effectively alleviated symptoms in some, but not all affected individuals, leaving clinicians to implement trial-and-error approach to treatment. In this review, we discuss recent experimental evidence from both preclinical and human studies that suggest imbalance of excitation/inhibition (E/I) in the fronto-striatal circuitry during early development may lead to enduring neuroanatomical abnormality of the circuitry, causing persistence of ADHD symptoms in adulthood. We propose a model of precision medicine care that includes E/I balance as a candidate biomarker for ADHD, development of GABA-modulating medications, and use of magnetic resonance spectroscopy and scalp electrophysiology methods to monitor the effects of treatments on shifting E/I balance throughout the lifespan.

Successful learning requires the control of attention to monitor performance and compare actual versus expected outcomes. Neural activity in the ventral tegmental area (VTA) has been linked to attention control in animals. However, it is unknown whether the strength of VTA connections is related to conflict monitoring in humans. To study the relationship between VTA connections and conflict monitoring, we acquired diffusion tensor imaging (DTI) data on 50 second language learners who we have previously studied. We performed probabilistic tractography to document VTA connections with the dorsal striatum and the anterior cingulate cortex (ACC), and administered the Flanker task in which subjects were required to monitor and report conflicts in visual stimuli. Reaction times (RTs) indexed students' conflict monitoring. Probabilistic tractography revealed distinct neural connections between the VTA and the dorsal striatum and ACC. Correlational analyses between tractography and flanker RTs revealed that the strength of VTA connections with the left caudate nucleus was negatively correlated with RTs recorded in the presence of conflicts. This provides the first evidence to suggest that VTA connections with the left caudate nucleus are related to conflict monitoring in humans.

Executive function (EF) skills enhance learning across domains, and are particularly linked to the acquisition of a second language. Previous studies have shown that bilingual individuals show enhanced EF skills in cognitive tasks where they attended a targeted dimension of a stimulus while inhibiting other competing cues. Brain imaging revealed that bilingual young adults’ performances in the Stroop color-naming task were related to the volume of anterior cingulate cortex (ACC) and inferior frontal lobe. Subjects who had greater white-matter in the frontal cortex showed enhanced performances in the same task, suggesting that brain fiber pathways connecting ACC to the frontal region may be related to the Stroop color-naming task. No studies to date have examined the tissue properties of brain fiber pathways connecting these brain regions and their association with subjects’ EF performances. Importantly, there are no data establishing whether bilingual subjects exhibit different reaction times when words are presented in their first versus second language. To study these questions, we used behavioral and unbiased whole-brain analyses, recruiting 21 Chinese students. Using the Stroop color-naming task, we measured subjects’ reaction times (RTs) in which color names were displayed using fonts that matched the named color (congruent task) or mismatched the color (incongruent task). Students performed the task twice, first in English, the subjects’ second language, then in Chinese, the subjects’ primary language. Results from whole-brain analysis showed that students’ RTs in both the English and Chinese tasks were significantly correlated with the mode of anisotropy (MO) in a brain cluster containing the forceps minor and anterior thalamic radiation in the right hemisphere. We also found that fractional anisotropy (FA) significantly predicted students’ RTs, with higher FA predicting shorter RT. Taken together, our findings demonstrate that right forceps minor and anterior thalamic radiation predict EF skills, suggesting that this brain feature may be important for young bilingual adults using their first and second languages to direct their attention when conflicting cues are present.

Adult human brains retain the capacity to undergo tissue reorganization during second-language learning. Brain-imaging studies show a relationship between neuroanatomical properties and learning for adults exposed to a second language. However, the role of genetic factors in this relationship has not been investigated. The goal of the current study was twofold: (i) to characterize the relationship between brain white matter fiber-tract properties and second-language immersion using diffusion tensor imaging, and (ii) to determine whether polymorphisms in the catechol-O-methyltransferase (COMT) gene affect the relationship. We recruited incoming Chinese students enrolled in the University of Washington and scanned their brains one time. We measured the diffusion properties of the white matter fiber tracts and correlated them with the number of days each student had been in the immersion program at the time of the brain scan. We found that higher numbers of days in the English immersion program correlated with higher fractional anisotropy and lower radial diffusivity in the right superior longitudinal fasciculus. We show that fractional anisotropy declined once the subjects finished the immersion program. The relationship between brain white matter fiber-tract properties and immersion varied in subjects with different COMT genotypes. Subjects with the Methionine (Met)/Valine (Val) and Val/Val genotypes showed higher fractional anisotropy and lower radial diffusivity during immersion, which reversed immediately after immersion ended, whereas those with the Met/Met genotype did not show these relationships. Statistical modeling revealed that subjects' grades in the language immersion program were best predicted by fractional anisotropy and COMT genotype.

Current methods to promote growth of cultured neurons use two-dimensional (2D) glass or polystyrene surfaces coated with a charged molecule (e.g. poly-L-lysine (PLL)) or an isolated extracellular matrix (ECM) protein (e.g. laminin-1). However, these 2D surfaces represent a poor topological approximation of the three-dimensional (3D) architecture of the assembled ECM that regulates neuronal growth in vivo. Here we report on the development of a new 3D synthetic nanofibrillar surface for the culture of neurons. This nanofibrillar surface is composed of polyamide nanofibers whose organization mimics the porosity and geometry of the ECM. Neuronal adhesion and neurite outgrowth from cerebellar granule, cerebral cortical, hippocampal, motor, and dorsal root ganglion neurons were similar on nanofibers and PLL-coated glass coverslips; however, neurite generation was increased. Moreover, covalent modification of the nanofibers with neuroactive peptides derived from human tenascin-C significantly enhanced the ability of the nanofibers to facilitate neuronal attachment, neurite generation, and neurite extension in vitro. Hence the 3D nanofibrillar surface provides a physically and chemically stabile cell culture surface for neurons and, potentially, an exciting new opportunity for the development of peptide-modified matrices for use in strategies designed to encourage axonal regrowth following central nervous system injury.