ORIGINAL RESEARCH article
Front. Behav. Neurosci.
Sec. Learning and Memory
Volume 19 - 2025 | doi: 10.3389/fnbeh.2025.1631236
tDCS-Induced Enhancement of Cognitive Flexibility in Autism: Role of Frontal Lobe and Associated Neural Circuits
Provisionally accepted
Yanan Han1
Anqin Dong1Chenyi Xia2Zhe Zhang1Wenjing Hu1
Tingli He1Xinxin Cui1Chengming Xu1Hongyan Xu1Zhangying Zhou1Danmeng Cheng1Shuo Zhang1Liguo Li1Youcai Tang1
Pengyuan Zheng1
Xianwen Dong1*- 1Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- 2Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and restricted, repetitive behaviors (RRBs). These symptoms may stem from cognitive flexibility deficits, with dysfunction in the prefrontal cortex (PFC) and related neural circuits proposed as underlying mechanisms. Objective: This study examined whether transcranial direct current stimulation (tDCS) could enhance PFC activity and functional connectivity, thereby improving cognitive flexibility in a valproic acid (VPA)-induced ASD rat model. Methods: Pregnant Sprague-Dawley rats were administered VPA (600 mg/kg, E12.5) or saline. VPA-exposed offspring exhibiting curved tails received tDCS and underwent behavioral tests, including the three-chamber social interaction test and cross-maze rule-shifting task, while local field potentials (LFPs) were recorded. Immunohistochemistry was performed to evaluate microglial activation (Iba1+) and synaptic density (PSD95). Results: VPA-exposed offspring displayed significant social interaction deficits and impaired cognitive flexibility, alongside disrupted functional connectivity in frontal-striato-hippocampal circuits. Neuroinflammatory analysis revealed elevated Iba1+ microglial density (p < 0.05) and increased PSD95 expression (p < 0.05). After tDCS intervention, VPA rats exhibited restored sociability and cognitive performance, normalized functional connectivity, and significantly reduced microglial activation (p < 0.05), though PSD95 levels were unaffected. Conclusion: Our results indicate that tDCS ameliorates ASD-like phenotypes in VPA rats, potentially through microglial suppression and PFC network synchronization. These findings support neuromodulation as a promising therapeutic approach for ASD-related cognitive dysfunction.
Keywords: Autism Spectrum Disorder, cognitive flexibility, tDCS, Dorsolateral prefrontal, hippocampal, Striatum
Received: 19 May 2025; Accepted: 17 Jul 2025.
Copyright: © 2025 Han, Dong, Xia, Zhang, Hu, He, Cui, Xu, Xu, Zhou, Cheng, Zhang, Li, Tang, Zheng and Dong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xianwen Dong, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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