Towards the identification and optimization of the "dose-response" relationship of transcranial direct current stimulation

Transcranial direct current stimulation (tDCS) is being investigated as a therapeutic tool in several neuropsychiatric disorders, but its mechanisms of action remain incompletely understood and its effectiveness is highly variable from subject to subject. Some of this inter-subject variance is thought to stem from individual differences in head anatomy, which result in different electric field distributions across individuals for the same stimulation settings. In a recent block-randomized, sham-controlled pilot study, 18 older adults with mild-to-moderate motor and cognitive impairments underwent a 2-week, 10-session intervention of 2 mA bipolar tDCS with the anode over the left dorsolateral prefrontal cortex (DLPFC) and cathode over the right supraorbital region (anodal F3 vs. FP2 using sponge electrodes in the 10-20 EEG system). tDCS, compared to sham stimulation, improved average cognitive-motor performance over a two-week follow-up. For a subset of 12 participants from this cohort who underwent structural brain MRIs at baseline, we derived tDCS-induced electric field properties using MRI-derived realistic, individualized finite element modeling. We hypothesized that the electric field component orthogonal (En) to the cortex over the left DLPFC would correlate with observed cognitive-motor improvements. Across the 12 subjects the average tDCS-induced electric field over the target area was highly variable with a standard deviation of the surface average En over the left DLPFC of 21% of the mean. For those subjects who were randomized to tDCS intervention (n=6), those who exhibited greater improvement in cognitive-motor performance were exposed to greater normal component of the tDCS electric field averaged over the left DLPFC (r95 % [isin] [-0.99,-0.59]). In contrast, averaged over the right DLPFC, En was a poor predictor of outcome (r95 % [isin] [-0.08,0.97]), as was the amplitude of the current injected (a widely adopted dosing parameter). In light of these results, we conducted a retrospective modeling experiment using personalized montage optimization algorithms to achieve a desired En amplitude over the left DLPFC. The optimized montages induced an average En on the left DLPFC comparable to the bipolar montages, but with half the variability (standard deviation was 11% compared to 21% with bipolar montages). In addition, these results suggest that optimized multichannel montages afford more focal targeting, with lower "spill-over" of electric field onto other cortical areas. These proof-of-concept results, though based upon a small sample size, indicate that assessment of the E-field distribution is critical when evaluating the effects of tDCS intervention. They also reinforce the importance of controlled cortical electric field dosing in tDCS and the potential advantages of optimized multichannel stimulation. Main findings: O_LIThe lDPFC averaged normal component of the electric field correlated with cognitive-motor improvements following tDCS intervention. C_LIO_LIIn older adults, head and brain anatomical differences resulted in high inter-subject variability of tDCS-induced electric fields. C_LIO_LItDCS montages optimized from modeling and delivered via multichannel electrode arrays can control variance and maximize electric field on target, while minimizing effects elsewhere. C_LI