Author:

Abstract:

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation method that is considered as treatment for a wide range of neurological and psychiatric disorders. While tDCS is becoming increasingly more popular, we have a limited understanding of the technique's underlying neurophysiological mechanisms. Ever since the emergence of tDCS, it has been generally assumed that the weak electric field in the cerebral cortex (the transcranial mechanism) was responsible for observed effects. More recently, it has been hypothesized tDCS's high electric field in the scalp (the transcutaneous mechanism) may activate peripheral nerves, providing an alternative mechanism through which tDCS could exert its effects. Despite the profound evidence that peripheral nerves are activated in tDCS, their potential contribution to tDCS effects has never been systematically investigated, is not controlled for in experiments and seems to have been overlooked by the field. To investigate the transcranial and transcutaneous mechanisms of tDCS, a minimally-restrictive awake rat model of tDCS was designed using epicranial electrodes to deliver currents directly to the brain and subcutaneous electrodes at peripheral sites. Characterization experiments showed that all electrodes have a stable conductivity over time and that experimental blinding with regards to the stimulation condition is possible. Next, the rat model was used to investigate tDCS's effects on passive avoidance task (PAT) learning and to dissect the transcranial and transcutaneous involvments in any effects. In contrast to previous work by other groups, PAT learning was not significantly changed by 30 minutes of tDCS at 0.25 mA. Consistent with that finding, PAT learning was also not altered significantly in the transcranial-only and transcutaneous-only stimulation groups; the groups in which the transcranial and transcutaneous pathways of tDCS were stimulated in an isolated manner. In a follow-up study, the PAT was performed with a transcutaneous-only group that received 30 minutes of tDCS at 2 mA, to more closely match the stimulation amplitude used on the scalp in human tDCS. In this group, in which the cathodal electrode was implanted over the third occipital nerve, PAT memory retention was significantly improved compared to the sham group. This indicates that peripheral nerve stimulation with stimulation amplitudes relevant for human tDCS experiments is capable of modulating learning and memory. More fundamental research and improved experimental design of clinical trials are necessary to shed light on the role of the transcranial and transcutaneous mechanisms in observed tDCS effects. This improved mechanistic understanding of tDCS will allow us to improve reproducibility and efficacy and will enable more rationalized clinical trial designs.