Physiological and modeling evidence for focal transcranial electrical brain stimulation in humans: a basis for high-definition tDCS

Abstract

Transcranial Direct Current Stimulation (tDCS) is a non-invasive, low-cost, well-tolerated technique producing lasting modulation of cortical excitability. Behavioral and therapeutic outcomes of tDCS are linked to the targeted brain regions, but there is little evidence that current reaches the brain as intended. We aimed to: (1) validate a computational model for estimating cortical electric fields in human transcranial stimulation, and (2) assess the magnitude and spread of cortical electric field with a novel High-Definition tDCS (HD-tDCS) scalp montage using a 4 × 1-Ring electrode configuration. In three healthy adults, Transcranial Electrical Stimulation (TES) over primary motor cortex (M1) was delivered using the 4 × 1 montage (4 × cathode, surrounding a single central anode; montage radius ~3 cm) with sufficient intensity to elicit a discrete muscle twitch in the hand. The estimated current distribution in M1 was calculated using the individualized MRI-based model, and compared with the observed motor response across subjects. The response magnitude was quantified with stimulation over motor cortex as well as anterior and posterior to motor cortex. In each case the model data were consistent with the motor response across subjects. The estimated cortical electric fields with the 4 × 1 montage were compared (area, magnitude, direction) for TES and tDCS in each subject. We provide direct evidence in humans that TES with a 4 × 1-Ring configuration can activate motor cortex and that current does not substantially spread outside the stimulation area. Computational models predict that both TES and tDCS waveforms using the 4 × 1-Ring configuration generate electric fields in cortex with comparable gross current distribution, and preferentially directed normal (inward) currents. The agreement of modeling and experimental data for both current delivery and focality support the use of the HD-tDCS 4 × 1-Ring montage for cortically targeted neuromodulation.

Fig. 1

High-resolution computational models individualized from anatomical MRI. Top: The entire modeling work-flow preserved the resolution of the MRI scans (1 mm). Skin, skull, CSF, gray, and white matter masks for each individual (2 males, ages 33–40 years; see Methods). Bottom: The scalp electrode position is displayed relative to the underlying tissues for each subject (anode C3).

Fig. 2

Validation of stimulation intensity: We modeled Transcranial Electrical Stimulation (TES) with a 50-µs pulse, using the High-Definition 4×1 Ring electrode montage (HD-TES), with the center ‘active’ electrode at position C3 (primary motor cortex hand area). Modeling data are displayed together with sample, overlaid waveforms representative of the mean amplitude recorded experimentally. The left panel; A (i), B (i), C (i) shows a range of stimulus intensities across subjects necessary to have comparable peak cortical electric field in M1. These predictions were confirmed with experimental data, where substantial input voltage differences were required to produce comparable amplitude MEPs. The right panel; A (ii), B (ii), C (ii) shows the results from the same intensity stimulation across subjects. The model data show a vastly different amount of current delivered to the cortex across subjects. Subject A has minimal current delivery, whereas Subjects B and C have strong current delivery. The model predictions are again consistent with the experimental data showing no evoked responses in Subject A, and strong evoked responses in subjects B and C.

Fig. 3

Modeling and experimental data (overlaid waveforms) from one subject (Subject A), illustrating the effect of TES at and away from C3 on predicted current density in M1 and corresponding MEPs in the hand. In addition to the C3 position, directly over primary motor cortex, the TES 4×1 montage was positioned in two anterior and two posterior positions, in each case moving away from the C3 position by approximately the distance of the circle radius (~3 cm). The four return ‘ring’ electrodes were also positioned using the 10/20 EEG system. Finite element analysis predicted brain current flow for each montage: the resulting cortical electric field magnitude (false color map) are shown in each case. In all three cases, the model predicts that High-Definition TES results in significant brain stimulation (>30% of peak) restricted to inside the ring perimeter, under the active center electrode. In this way, only the C3 centered case produces significant stimulation of motor regions.

Fig. 4

Sample overlaid MEP waveforms from Subject A in response to TES (left panel) and TMS (right panel) with intensity adjusted to elicit 0.3–0.5 mV amplitude. Consistent responses occurred with stimulation over C3, but the same intensity stimulation moved to the 1-R distance from C3 could only weakly generate MEPs, and no response could be elicited with stimulation at the 2-R positions. This effect was independent of movement in the anterior or posterior directions, and no difference in this spatial relationship could be distinguished between TES and TMS. This provides direct evidence that the 4×1 montage can deliver current to cerebral cortex without substantial current spread.

Fig. 5

High-resolution computer simulation prediction of relative focality of Transcranial Electrical Stimulation (TES) and transcranial Direct Current Stimulation (tDCS) using the High-Definition 4×1 Ring Configuration. Using the identical High-Definition 4×1 electrode montage centered on C3, the relative brain stimulation focality using a high-voltage short-pulse (TES, A, same conditions as Fig. 2 plotted full scale) and low-intensity direct current (tDCS, B) was calculated (see Methods). In each case, the resulting cortical electric field magnitude is plotted relative to the respective peak cortical electric field induced for each waveform: 163 V/m for TES, and 0.11 V/m for tDCS. The false-color maps thus indicate the spatial distribution of brain stimulation and relative focality in each case. For both TES_4×1 and tDCS_4×1: 1) The relative brain surface activation (>30% peak) was generally restricted to inside the ring (A.1, B.1) but the relative spatial distribution was slightly broader for tDCS; 2) The electric field was slightly more superficial for the TES_4×1 waveform (A.2, B.2); 3) The peak cortical electric field (A.1b inset, B.1b inset) was on gyri crowns, interestingly in both cases on the same gyrus slightly posterior to the center electrode; 4) Consideration of normal direction current (A.1a inset, B.1a inset) red: inward; green: no normal current; blue: outward) did not change the above findings.