I_h interacts with somato-dendritic structure to determine frequency response to weak alternating electric field...

Transcranial current stimulation (tCS) modulates brain dynamics using weak electric fields. Given the pathological changes in brain network oscillations in neurological and psychiatric illnesses, using alternating electric field waveforms that engage rhythmic activity has been proposed as a targeted, network-level treatment approach. Previous studies have investigated the effects of electric fields at the neuronal level. However, the biophysical basis of the cellular response to electric fields has remained limited. Here, we characterized the frequency-dependent response of different compartments in a layer V pyramidal neuron to exogenous electric fields to dissect the relative contributions of voltage-gated ion channels and neuronal morphology. Hyperpolarization-activated cation current (I_h) in the distal dendrites was the primary ionic mechanism shaping the model's response to electric field stimulation and caused subthreshold resonance in the tuft at 20 ± 4 Hz. In contrast, subthreshold I_h-mediated resonance in response to local sinusoidal current injection was present in all model compartments at 11 ± 2 Hz. The frequencies of both resonance responses were modulated by I_h conductance density. We found that the difference in resonance frequency between the two stimulation types can be explained by the fact that exogenous electric fields simultaneously polarize the membrane potentials at the distal ends of the neuron (relative to field direction) in opposite directions. Our results highlight the role of I_h in shaping the cellular response to electric field stimulation and suggest that the common model of tCS as a weak somatic current injection fails to capture the cellular effects of electric field stimulation. NEW & NOTEWORTHY Modulation of cortical oscillation by brain stimulation serves as a tool to understand the causal role of network oscillations in behavior and is a potential treatment modality that engages impaired network oscillations in disorders of the central nervous system. To develop targeted stimulation paradigms, cellular-level effects must be understood. We demonstrate that hyperpolarization-activated cation current (I_h) and cell morphology cooperatively shape the response to applied alternating electric fields.