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

George Zacharopoulos Orcid Logo, Masoumeh Dehghani, Beatrix Krause-Sorio, Jamie Near, Roi Cohen Kadosh

PLOS Biology, Volume: 23, Issue: 7, Start page: e3003200

Swansea University Author: George Zacharopoulos Orcid Logo

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DOI (Published version): 10.1371/journal.pbio.3003200

Abstract

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 t...

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Published in: PLOS Biology
ISSN: 1544-9173 1545-7885
Published: Public Library of Science (PLoS) 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa69894
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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&#x2014;high-frequency transcranial random noise stimulation (tRNS)&#x2014;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. 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spelling 2025-07-04T12:32:41.0310060 v2 69894 2025-07-04 Functional connectivity and GABAergic signaling modulate the enhancement effect of neurostimulation on mathematical learning 7abcfe5e6fd29d20e2c53eff9a4098d1 0000-0003-0574-866X George Zacharopoulos George Zacharopoulos true false 2025-07-04 PSYS 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. Journal Article PLOS Biology 23 7 e3003200 Public Library of Science (PLoS) 1544-9173 1545-7885 1 7 2025 2025-07-01 10.1371/journal.pbio.3003200 COLLEGE NANME Psychology School COLLEGE CODE PSYS Swansea University Another institution paid the OA fee European Research Council Grant: Learning&Achievement 338065; Wellcome Trust Grant: 0883781 2025-07-04T12:32:41.0310060 2025-07-04T12:16:04.0912825 Faculty of Medicine, Health and Life Sciences School of Psychology George Zacharopoulos 0000-0003-0574-866X 1 Masoumeh Dehghani 2 Beatrix Krause-Sorio 3 Jamie Near 4 Roi Cohen Kadosh 5 69894__34679__362170b37b8f41aa8cad0475e141cb33.pdf pbio.3003200.pdf 2025-07-04T12:16:04.0910148 Output 953839 application/pdf Version of Record true © 2025 Zacharopoulos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY). true eng http://creativecommons.org/licenses/by/4.0/
title Functional connectivity and GABAergic signaling modulate the enhancement effect of neurostimulation on mathematical learning
spellingShingle Functional connectivity and GABAergic signaling modulate the enhancement effect of neurostimulation on mathematical learning
George Zacharopoulos
title_short Functional connectivity and GABAergic signaling modulate the enhancement effect of neurostimulation on mathematical learning
title_full Functional connectivity and GABAergic signaling modulate the enhancement effect of neurostimulation on mathematical learning
title_fullStr Functional connectivity and GABAergic signaling modulate the enhancement effect of neurostimulation on mathematical learning
title_full_unstemmed Functional connectivity and GABAergic signaling modulate the enhancement effect of neurostimulation on mathematical learning
title_sort Functional connectivity and GABAergic signaling modulate the enhancement effect of neurostimulation on mathematical learning
author_id_str_mv 7abcfe5e6fd29d20e2c53eff9a4098d1
author_id_fullname_str_mv 7abcfe5e6fd29d20e2c53eff9a4098d1_***_George Zacharopoulos
author George Zacharopoulos
author2 George Zacharopoulos
Masoumeh Dehghani
Beatrix Krause-Sorio
Jamie Near
Roi Cohen Kadosh
format Journal article
container_title PLOS Biology
container_volume 23
container_issue 7
container_start_page e3003200
publishDate 2025
institution Swansea University
issn 1544-9173
1545-7885
doi_str_mv 10.1371/journal.pbio.3003200
publisher Public Library of Science (PLoS)
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hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str School of Psychology{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}School of Psychology
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description 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.
published_date 2025-07-01T05:29:23Z
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