Neural Mechanisms of tDCS: Insights from an In-Vivo Rodent Model with Realistic Electric Field Strengths

IntroductionTranscranial direct current stimulation (tDCS) is a non-invasive neuromodulation method using low amplitude current (1-2 mA) to create weak electric fields (<1 V/m) in the brain, influencing cognition, motor skills, and behavior. However, the neural mechanisms remain unclear, as prior studies used high electric field strengths (10-40 V/m) unrepresentative of human tDCS. ObjectiveThis study aimed to develop an in-vivo rat model replicating human tDCS electric field strengths to examine effects of weak electric fields on cortical neurons. MethodCurrents of 0.005-0.3 mA were applied in 9 rats, generating electric fields of 0.5-35 V/m in the somatosensory cortex. Neural activity across cortical layers was recorded using a multichannel silicone probe. Somatosensory evoked potentials (SSEP) elicited by foot shocks assessed membrane polarization. Regular spiking (RS) and fast-spiking (FS) neurons were identified via spike shapes. Effects of tDCS on SSEP, spontaneous spiking activity (SSA), and evoked spiking activity (ESA) were analyzed. ResultsAnodal tDCS caused hyperpolarization (SSEP increase) in superficial layers and depolarization (SSEP decrease) in deeper layers, reversing asymmetrically for cathodal stimulation. Weak fields (<1 V/m) altered SSA in RS but not FS neurons, while stronger fields affected ESA in RS neurons. Effects correlated with field strength and were well described by linear mixed-effect models. Changes in SSA were correlated with changes in SSEP. ConclusionThis study demonstrates that realistic tDCS fields induce complex cortical polarization patterns linked to SSA changes. Increasing electric field strength amplifies effects, suggesting higher amplitude tDCS could enhance efficacy in humans. HighlightsO_LINewly developed in-vivo rodent model to replicate the weak electric field strengths characteristic of human tDCS, probe localized membrane polarization effects and simultaneously monitor spontaneous and evoked spiking activity. C_LIO_LIResults provide the first direct in-vivo confirmation of several tDCS mechanistic predictions derived from computational models and brain slice work. C_LIO_LIComplex Membrane Polarization Patterns: tDCS induces simultaneous hyperpolarization and depolarization in distinct neuronal compartments. C_LIO_LINeuron-Specific Effects: Weak electric fields preferentially modulate excitatory neurons, with no significant impact on inhibitory neurons at low electric field strengths. C_LIO_LIPolarity asymmetric effects: Anodic stimulation produces stronger effects than cathodic stimulation. C_LIO_LIMembrane polarization is linked to changes in spiking activity: Changes in membrane polarization are correlated with changes in spontaneous spiking activity. C_LIO_LIAll the tDCS neural mechanisms showed effects that were linearly related to electric field strength, underscoring the translational importance of novel tDCS protocols that can increase electric field strength, potentially improving the robustness and reproducibility of tDCS protocols in humans. C_LI