Weak electric fields of deep brain stimulation can entrain spiking in multi-compartment cortical neuron models

Background: Deep brain stimulation (DBS) is widely used to treat neurological disorders, but how it exerts its therapeutic effects remains an open question. Although DBS primarily acts through stimulated subcortical structures and their networks, recent studies have demonstrated that cortical electric field (E-field) strengths generated during DBS are comparable to, and can exceed, those shown to modulate neuronal activity with transcranial alternating current stimulation. We therefore investigated whether and how these weak DBS fields can directly modulate cortical spike timing. Methods: We used multi-compartment computational models of five neuron types across all cortical layers and exposed them to E-fields modeled as DBS pulses. E-field amplitudes spanned the typical range of cortical E-field strengths during DBS, while frequency and orientation were varied. Entrainment was assessed using peri-stimulus time histograms and quantified by the phase locking value (PLV). Results: Weak DBS fields modulated spike timing of some neurons by either increasing or decreasing the likelihood of firing immediately following the stimulation pulse. This modulation reflected entrainment to the stimulation, with the PLV increasing with E-field amplitude and frequency. The magnitude and direction of spike-timing modulation varied across neuron types and depended on the orientation of the field. Conclusion: These findings suggest that cortical E-fields of DBS may directly influence activity of some cortical neurons, alongside the established indirect cortical effects mediated by subcortical targets and their networks. This provides a new perspective on how DBS may influence cortical activity and offers insights into its potential mechanisms of therapeutic and/or side effects.