Modulation of slow and fast oscillations by direct current stimulation in the cerebral cortex in vitro

Non-invasive brain stimulation techniques, such as transcranial direct current stimulation, are used in the treatment of neurological disorders. However, the mechanisms by which electric fields modulate cortical network activity are only partially understood. Our aim was to determine the modulation of spontaneous cortical activity by static electric fields and their underlying network mechanisms, which we investigated in vitro and in silico. Neocortical slices were exposed to constant fields of varying intensities and directions. We measured their effect on slow oscillations (SOs, <1 Hz), which consist of Up (active) and Down (silent) states, and on the high-frequency content (β: 15-30 Hz, γ: 30-90 Hz) during Up states. We found that DC fields ranging from -6 to +6 V/m induced an exponential increase in the frequency of SOs through the regulation of neuronal excitability and the duration of Down states, while hardly affecting Up state duration. A computational model based on the mean-field theory of attractor dynamics provided a mechanistic and quantitative description of the network dynamics underlying such precise modulation of slow oscillatory frequency. The modulation of high frequencies by positive DC fields was less consistent, the high-frequency power varying with the intensity of the fields only in a fraction of slices. Negative DC fields of increasing intensities progressively and effectively reversed the kainate-induced high-frequency power. DC fields precisely modulate emergent cortical network activity even through millivolt-scale effects on individual neurons. This effect is specific for different parameters of cortical oscillations. We discuss the underlying mechanisms and implications. KEY POINTS: We studied the impact that direct current (DC) electric fields had on the slow (<1 Hz) and fast (β: 15-30 Hz and γ: 30-90 Hz) frequencies spontaneously generated by the cerebral cortex in vitro. We found that weak (<6 V/m) DC fields can control the frequency of slow oscillations generated by the cortical network, and we explored the underlying mechanisms both experimentally and in a computer model. We conclude that, despite producing only millivolt-scale effects at the single-neuron level, DC fields can robustly modulate cortical population activity, with efficacy varying across frequency bands. These findings are relevant for the design of effective tDCS protocols for therapeutical purposes.