MOTOR CORTEX TDCS SELECTIVELY INHIBITS TRIGEMINOCERVICAL COMPLEX NEURONS IN A SEX- AND HORMONE-DEPENDENT MANNER

Neurostimulation of the motor cortex via transcranial direct current stimulation (tDCS) is a promising therapeutic strategy for chronic migraine, yet its underlying mechanisms remain poorly understood. This study aimed to determine how sex and hormonal status influence tDCS efficacy and to decipher the underlying cellular pathways within the trigeminocervical complex (TCC)—a pivotal neuroanatomical hub where orofacial and meningeal nociceptive afferents converge.
Using a rodent model, electrodes were implanted over the motor M1 and occipital cortex of anesthetized male, cycling female, and ovariectomized (OVX) rats. A single tDCS session (200 µA-20 min) was applied. We conducted unitary extracellular recordings of TCC neurons to evaluate responses to nociceptive stimuli and performed immunohistochemical analysis of phosphorylated ERK (p-ERK) expression.
Our findings demonstrate that M1-tDCS induces a robust inhibition of TCC neuron activity in response to electrical C-fiber stimulation in both males and cycling females but not in OVX females. Furthermore, tDCS efficacy was significantly more pronounced in females during the Proestrus/Estrus phases compared to the Metestrus/Diestrus, suggesting that sexual hormones act as critical facilitators of the neuromodulatory response.
Immunohistochemical analysis also revealed that a single tDCS session triggers a bilateral overexpression of p-ERK within the TCC. Notably, significant microglial activation (p-ERK+/Iba1+) was observed in cycling and OVX females but was absent in males.
These findings demonstrate that tDCS efficacy is dictated by sex and hormonal status. The absence of a microglial signature in males, despite clear electrophysiological inhibition, reveals a profound sexual dimorphism in the neuromodulatory circuits recruited by tDCS.