Both intermittent (iTBS) and continuous theta-burst stimulation (cTBS) improved social deficits and repetitive behaviors in rats exposed to valproic acid.
cTBS effectively reduced anxiety-like behaviors, while iTBS significantly enhanced learning and memory.
iTBS primarily influenced inflammatory immune responses and energy metabolism.
cTBS predominantly affected oxidative stress, lipid metabolism, and nucleotide metabolism.
Both stimulation protocols suppressed the hyperactivated PI3K/AKT/mTOR signaling pathway.
A potential interaction between the GH/IGF-1 axis and the gut microbiome in autism spectrum disorder was identified, with differential modulation by iTBS and cTBS.
Simplified
OBJECTIVE: , including intermittent (iTBS) and continuous (cTBS) protocols, is a promising neuromodulatory intervention for autism spectrum disorder (ASD). This study aims to elucidate the therapeutic mechanisms of iTBS and cTBS for ASD.
METHODS: Prenatal valproic acid-induced ASD rats were established and were randomized into VPA, VPA + iTBS, and VPA + cTBS groups, with a saline group as control. Core and comorbid ASD behaviors in rats were assessed. Multi-omics analyses included 16 S rRNA sequencing of cecal contents, non-targeted fecal metabolomics, and prefrontal cortex transcriptomics. Key pathways were validated via Western blot, ELISA, and immunofluorescence. Integrative analyses correlated multi-omics data with neuroendocrine findings.
RESULTS: Behavioral assessments demonstrated that both iTBS and cTBS significantly ameliorated social deficits and repetitive behaviors in VPA-exposed rats. However, protocol-specific effects on comorbidities were observed: cTBS, but not iTBS, effectively alleviated anxiety-like behaviors, whereas iTBS, but not cTBS, significantly improved learning and memory. The multi-omics approach demonstrated that iTBS primarily modulated inflammatory immune responses and energy metabolism, while cTBS predominantly regulated oxidative stress, lipid metabolism, and nucleotide metabolism. Both interventions suppressed the hyperactivated PI3K/AKT/mTOR signaling pathway, an effect potentially linked to the normalization of hypothalamic-pituitary axis function. Furthermore, we identified a potential interplay between the GH/IGF-1 axis and the gut microbiome in ASD, which was differentially modulated by iTBS and cTBS.
CONCLUSION: iTBS modulated inflammatory-immune responses and energy metabolism, while cTBS regulated oxidative stress, lipid metabolism, and nucleotide metabolism. The inhibition of the central GH/ by both protocols may involve their specific regulation of distinct gut microbiota communities.
GRAPHICAL ABSTRACT: [Image: see text]
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-026-06096-2.
Key numbers
F = 36.02,< 0.0001
Increase in sociability index
One-way ANOVA analysis of sociability index across groups.
F = 15.8,< 0.0001
Decrease in buried marbles
One-way ANOVA analysis of marble burying test results.
< 0.001
Decrease in pyknotic cells
Quantitative analysis of neuronal morphology following treatments.
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Declarations. Ethics statement: This study was approved by Animal Experiments and Experimental Animal Welfare Committee of Capital Medical University (AEEI-2024-073) and comply with the ARRIVE guidelines and the National Research Council’s Guide for the Care and Use of Laboratory Animals. Conflict of interest: The authors declare no conflicts of interest.
PubMed
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