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Published on: June 17, 2025
1 Hz Low-Frequency Repetitive Transcranial Magnetic Stimulation Ameliorates Epilepsy by Suppressing Interferon-γ
Donghui Lin1, Duan Wang2, Nong Xiao1
1Department of Rehabilitation Children's Hospital of Chongqing Medical University, National Clinical Research Center for Children and Adolescents' Health and Diseases, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing, China.
Aims:
We aim to investigate the impact of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) on activated microglia in temporal lobe epilepsy (TLE), which exacerbate seizures and memory problems, and to explore the molecular mechanisms and clinical potential of LF-rTMS for TLE treatment.
Methods:
We tested 0.3, 0.5, 1 Hz LF-rTMS in kainic acid (KA)-induced TLE mice, assessing EEG, inflammation, synaptic phagocytosis, memory, scRNA-seq, and IFN-γ neutralizing antibodies. SnRNA-seq of human hippocampal sclerosis (HS) tissues confirmed relevance.
Results:
In KA-induced TLE mice, 1 Hz LF-rTMS decreased seizures, neuroinflammation, and hippocampal synaptic phagocytosis, while enhancing memory. These effects were linked to increased microglial IFN-γ signaling (activating STAT2 and inhibiting CADM1/2/3), which were negated by IFN-γ blockade. SnRNA-seq of human HS tissues revealed elevated IFN-γ signaling in DAM-like cells, indicating clinical relevance.
Conclusion:
Our study indicates that 1 Hz LF-rTMS is a promising treatment for TLE, potentially reducing seizures and cognitive issues by affecting microglial function. Our findings show that IFN-γ signaling triggers STAT2 activation, which is strongly linked to the increased expression of IFN-γ signature DAM and the decreased expression of CADM1/2/3 in DAM, thus playing a role in the neuroprotective effects of 1 Hz LF-rTMS. These findings reveal a new LF-rTMS mechanism and offer insights for targeted therapies in drug-resistant epilepsy.
Insights
Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) at 1 Hz effectively reduced seizures and memory deficits in temporal lobe epilepsy (TLE) mouse models. This treatment impacts microglial function via interferon-gamma (IFN-γ) signaling, offering a promising therapeutic avenue for TLE.
Area of Science:
- Neuroscience
- Epilepsy Research
- Molecular Biology
Background:
- Temporal lobe epilepsy (TLE) is characterized by recurrent seizures and cognitive impairments.
- Activated microglia contribute to TLE pathogenesis, exacerbating seizures and memory problems.
- Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) is being explored as a potential therapeutic intervention for neurological disorders.
Purpose of the Study:
- To investigate the impact of LF-rTMS on activated microglia in TLE.
- To elucidate the molecular mechanisms underlying LF-rTMS effects in TLE.
- To explore the clinical potential of LF-rTMS for TLE treatment.
Main Methods:
- Kainic acid (KA)-induced TLE mouse models were treated with varying frequencies of LF-rTMS (0.3, 0.5, 1 Hz).
- Assessments included electroencephalography (EEG), neuroinflammation markers, synaptic phagocytosis, memory tests, and single-cell RNA sequencing (scRNA-seq).
- Interferon-gamma (IFN-γ) neutralizing antibodies were used, and scRNA-seq of human hippocampal sclerosis (HS) tissues confirmed clinical relevance.
Main Results:
- 1 Hz LF-rTMS significantly decreased seizures, neuroinflammation, and hippocampal synaptic phagocytosis in TLE mice.
- Memory function was enhanced following 1 Hz LF-rTMS treatment.
- These beneficial effects correlated with increased microglial IFN-γ signaling, leading to STAT2 activation and inhibition of CADM1/2/3, which was reversed by IFN-γ blockade. Human HS tissues showed elevated IFN-γ signaling in disease-associated microglia (DAM)-like cells.
Conclusions:
- 1 Hz LF-rTMS demonstrates significant therapeutic potential for TLE, reducing seizures and cognitive deficits by modulating microglial function.
- The mechanism involves IFN-γ signaling, STAT2 activation, and altered expression of DAM markers and CADM1/2/3, contributing to neuroprotection.
- These findings reveal a novel mechanism for LF-rTMS and suggest targeted therapeutic strategies for drug-resistant epilepsy.
