Reply to Huang and Dong: Circuit insights unlock translational potential of peripheral electroacupuncture for epilepsy

We thank Junqing Dong (1) for the insightful comments on our study of GV14 electroacupuncture stimulation for epilepsy treatment (2). Our basic research primarily elucidates the precise circuit mechanism underlying electroacupuncture at specific somatic acupoints. GV14 electroacupuncture suppresses seizures via a defined caudal nucleus of the solitary tract (cNTS)–locus coeruleus–amygdala circuit. Indeed, bridging mechanistic discovery and clinical translation remains a primary challenge. Our work addresses a critical gap by delineating a targetable circuit linking peripheral stimulation to central seizure control, rather than asserting direct clinical equivalence with established therapies.

First, acute chemoconvulsant models are valuable for mechanistic investigations but cannot replicate the chronic remodeling and spontaneous recurrent seizures seen in drug-resistant epilepsy. The 4-hour seizure suppression observed likely reflects transient modulation rather than sustained control of chronically reorganized epilepsy networks. Epileptogenesis arises from maladaptive neural circuitry, and therapeutic efficacy requires long-term network restructuring and seizure threshold elevation (3, 4). Notably, thread-embedding acupuncture in chronic models produces cumulative, sustained seizure reduction, with effects comparable to those reported for vagus nerve stimulation (VNS) (5). However, the magnitude and durability of thread-embedding acupuncture’s effects relative to established VNS in our chronic epilepsy models with head-to-head comparison remain to be quantitatively determined.

Second, vagal dependence does not imply superiority over cervical VNS. However, electroacupuncture exhibits circuit-level specificity that is absent in conventional VNS, which indiscriminately activates mixed sensory and motor fibers, often leading to off-target side effects (6). GV14 stimulation selectively engages vagal afferents from defined somatic loci, producing functionally partitioned activation of the cNTS. This is evidenced by preferential recruitment of Dbh⁺ neurons rather than broadly activated glutamatergic populations. Consistent with emerging cNTS transcriptomic data (7), these defined neuronal populations are likely molecularly distinct, offering potential targets for future pharmacological intervention. Importantly, this targeted activation is associated with seizure suppression and reduced nociceptive sensitization, suggesting improved tolerability. Such circuit specificity provides a biologically grounded target for drug development and supports the concept that precision modulation may improve specificity and tolerability, although whether this translates into superior seizure control compared with VNS remains to be determined. These findings highlight circuit-level dissection as a prerequisite for rational clinical translation.

Third, regarding logistical and economic considerations, the superficial anatomical location of GV14 facilitates minimal-invasive translation. Unlike surgically implanted VNS devices, the cNTS neural subpopulation or circuit offers a well-defined substrate for next-generation neuromodulation. Emerging technologies, including microneedle arrays and focused ultrasound, may enable minimally invasive, circuit-specific activation (8, 9). These approaches could support closed-loop seizure control systems that deliver intervention only upon seizure detection, thereby preserving circuit responsiveness and reducing treatment burden, although current protocols may still require repeated interventions (10). Although formal cost-effectiveness analyses are premature, such noninvasive strategies may reduce surgical risks and long-term healthcare utilization.

In summary, our circuit mechanism-driven discovery provides a rational foundation for next-generation neuromodulation and pharmacological strategies, with the potential to overcome limitations of current invasive therapies. Future translational studies should therefore focus on developing novel therapeutic strategies, evaluating long-term efficacy in chronic spontaneous recurrent seizure models, and establishing formal cost-effectiveness analyses.