Abstract
BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation modality that can alter cortical excitability. However, it remains unclear how the subcellular elements of different neuron types are polarized by specific electric field (E-field) distributions. OBJECTIVE: To quantify neuronal polarization generated by tDCS in a multi-scale computational model. METHODS: We embedded layer-specific, morphologically-realistic cortical neuron models in a finite element model of the E-field in a human head and simulated steady-state polarization generated by conventional primary-motor-cortex-supraorbital (M1-SO) and 4 × 1 high-definition (HD) tDCS. We quantified somatic, axonal, and dendritic polarization of excitatory pyramidal cells in layers 2/3, 5, and 6, as well as inhibitory interneurons in layers 1 and 4 of the hand knob. RESULTS: Axonal and dendritic terminals were polarized more than the soma in all neurons, with peak axonal and dendritic polarization of 0.92 mV and 0.21 mV, respectively, compared to peak somatic polarization of 0.07 mV for 1.8 mA M1-SO stimulation. Both montages generated regions of depolarization and hyperpolarization beneath the M1 anode; M1-SO produced slightly stronger, more diffuse polarization peaking in the central sulcus, while 4 × 1 HD produced higher peak polarization in the gyral crown. The E-field component normal to the cortical surface correlated strongly with pyramidal neuron somatic polarization (R(2)>0.9), but exhibited weaker correlations with peak pyramidal axonal and dendritic polarization (R(2):0.5-0.9) and peak polarization in all subcellular regions of interneurons (R(2):0.3-0.6). Simulating polarization by uniform local E-field extracted at the soma approximated the spatial distribution of tDCS polarization but produced large errors in some regions (median absolute percent error: 7.9 %). CONCLUSIONS: Polarization of pre- and postsynaptic compartments of excitatory and inhibitory cortical neurons may play a significant role in tDCS neuromodulation. These effects cannot be predicted from the E-field distribution alone but rather require calculation of the neuronal response.