Decoding Gamma Oscillations in the Anterior Cingulate Cortex via iTBS: Unraveling the Mysteries of Chronic Non-Specific Low Back Pain

Hui JiangQiaohua WangChao Zhan^*Wei Cheng^*Zhengfei Ye

• Huangshi Hospital of Traditional Chinese Medicine, Huangshi, China

The chronicity of chronic nonspecific low back pain (CNSLBP) is closely linked to aberrant gamma oscillations (23-30 Hz) in the anterior cingulate cortex (ACC) and whole-brain network desynchronization. This study aimed to investigate the mechanisms and therapeutic efficacy of intermittent theta-burst stimulation (iTBS) in modulating ACC gamma oscillations and neuroplasticity to alleviate pain and comorbid emotional-cognitive symptoms. Integrating animal models and clinical trials, multimodal neuroimaging (fMRI/EEG), molecular analyses, and closed-loop neuromodulation techniques were employed. iTBS parameters were optimized (intensity: 120% resting motor threshold; timing: 5 Hz theta rhythm coupled with 50 Hz gamma pulses), with ACC subregions precisely localized using individualized functional connectivity mapping (rs-fMRI). Results demonstrated that iTBS bidirectionally regulated ACC excitatory/inhibitory (E/I) balance via NMDA receptor-mediated synaptic plasticity, suppressing pathological gamma synchronization (15% reduction in gamma power) and enhancing GABAergic transmission (upregulated GAD67 expression). Clinically, a single iTBS session transiently reduced pain intensity (VAS scores, *p* < 0.05), while 4-week repeated interventions prolonged analgesic effects (*p* < 0.05), though efficacy varied with patient heterogeneity (e.g., COMT/BDNF genotypes). Dynamic causal modeling (DCM) revealed that iTBS attenuated aberrant ACC-amygdala gamma connectivity (20% decrease in effect size) and strengthened ACC-insula theta-gamma cross-frequency coupling, improving emotional pain integration (*p* < 0.001). Safety analysis indicated iTBS was well-tolerated, with adverse event rates comparable to conventional repetitive transcranial magnetic stimulation (rTMS) (headache: 65% vs. 64%). These findings validate iTBS as a non-invasive neuromodulatory strategy for CNSLBP by remodeling ACC gamma oscillations and global network dynamics. Future research should integrate multimodal data and artificial intelligence to refine personalized protocols and explore synergistic interventions with virtual reality or spinal cord stimulation, advancing clinical translation from symptomatic relief to neuroplastic repair.