Functional connectivity and GABAergic signaling modulate the enhancement effect of neurostimulation on mathematical learning.

Effortful learning and practice are integral to academic attainment in areas like reading, language, and mathematics, shaping future career prospects, socioeconomic status, and health outcomes. However, academic learning outcomes often exhibit disparities, with initial cognitive advantages leading to further advantages (the Matthew effect). One of the areas in which learners frequently exhibit difficulties is mathematical learning. Neurobiological research has underscored the involvement of the dorsolateral prefrontal cortex (dlPFC), the posterior parietal cortex (PPC), and the hippocampus in mathematical learning. However, their causal contributions remain unclear. Moreover, recent findings have highlighted the potential role of excitation/inhibition (E/I) balance in neuroplasticity and learning. To deepen our understanding of the mechanisms driving mathematical learning, we employed a novel approach integrating double-blind excitatory neurostimulation-high-frequency transcranial random noise stimulation (tRNS)-and examined its effect at the behavioral, functional, and neurochemical levels. During a 5-day mathematical learning paradigm (n = 72) active tRNS was applied over the dlPFC or the PPC, and we compared the effects versus sham tRNS. Individuals exhibiting stronger positive baseline frontoparietal connectivity demonstrated greater improvement in calculation learning. Subsequently, utilizing tRNS to modulate frontoparietal connectivity, we found that participants with weaker positive baseline frontoparietal connectivity, typically associated with poorer learning performance, experienced enhanced learning outcomes following dlPFC-tRNS only. Further analyses revealed that dlPFC-tRNS improved learning outcomes for participants who showed reductions in dlPFC GABA when it was accompanied by a reduced positive frontoparietal connectivity, but this effect was reversed for participants who showed increased positive frontoparietal connectivity. Our multimodal approach elucidates the causal role of the dlPFC and frontoparietal network in a critical academic learning skill, shedding light on the interplay between functional connectivity and GABAergic modulation in the efficacy of brain-based interventions to augment learning outcomes, particularly benefiting individuals who would learn less optimally based on their neurobiological profile.