Frequency-dependent phase entrainment of cortical cell types during tACS: computational modeling evidence.

. Transcranial alternating current stimulation (tACS) enables non-invasive modulation of brain activity, holding promise for clinical and research applications. Yet, it remains unclear how the stimulation frequency differentially impacts various neuron types. Here, we aimed to quantify the frequency-dependent behavior of key neocortical cell types.. We used both detailed (anatomical multicompartments) and simplified (three compartments) single-cell modeling approaches based on the Hodgkin-Huxley formalism to study neocortical excitatory and inhibitory cells under various tACS intensities and frequencies within the 5-50 Hz range at rest and during basal 10 Hz activity.. L5 pyramidal cells (PCs) exhibited the highest polarizability at direct current, ranging from 0.21 to 0.25 mm and decaying exponentially with frequency. Inhibitory neurons displayed membrane resonance in the 5-15 Hz range with lower polarizability, although bipolar cells had higher polarizability. Layer 5 PC demonstrated the highest entrainment close to 10 Hz, which decayed with frequency. In contrast, inhibitory neurons entrainment increased with frequency, reaching levels akin to PC. Results from simplified models could replicate phase preferences, while amplitudes tended to follow opposite trends in PC.. tACS-induced membrane polarization is frequency-dependent, revealing observable resonance behavior. Whilst optimal phase entrainment of sustained activity is achieved in PC when tACS frequency matches endogenous activity, inhibitory neurons tend to be entrained at higher frequencies. Consequently, our results highlight the potential for precise, cell-specific targeting for tACS.