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

BackgroundTranscranial 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 affects various neuron types. ObjectiveTo quantify the frequency-dependent behavior of key neocortical cell types. MethodsWe 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-amplitude tACS frequencies within the 5-50 Hz range at rest and during basal 10 Hz activity. ResultsL5 pyramidal cells exhibited the highest polarizability at DC, ranging from 0.21 to 0.25mm 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 level akin to PC. Results from simplified models could replicate the phase preferences, while amplitudes tend to follow opposite trends in PC. ConclusiontACS-induced membrane polarization is frequency-dependent, revealing observable resonance behavior. This finding motivates further experimental studies of cell-specific frequency-dependent membrane responses to weak electric stimuli. Whilst optimal phase entrainment of sustained activity is achieved in PC when tACS frequency matches the activity, inhibitory neurons tend to be entrained at higher frequencies. Consequently, this presents the potential for precise, cell-specific targeting. O_LISingle-cell models of frequency response to tACS for a wide variety of neurons C_LIO_LISimplified and morphologically accurate models were compared C_LIO_LIPyramidal cells (PC) show resonant-like response close to intrinsic firing frequency C_LIO_LIEntrainement of GABAergic neurons increases with the frequency of tACS C_LIO_LIMembrane polarization resonance in GABAergic neurons within the 5-15 Hz range C_LI