Electric Field Model of Transcranial Electric Stimulation in Nonhuman Primates: Correspondence to Individual Motor Threshold

Abstract

Objective: To develop a pipeline for realistic head models of nonhuman primates (NHPs) for simulations of noninvasive brain stimulation, and use these models together with empirical threshold measurements to demonstrate that the models capture individual anatomical variability.

Methods: Based on structural MRI data, we created models of the electric field (E-field) induced by right unilateral (RUL) electroconvulsive therapy (ECT) in four rhesus macaques. Individual motor threshold (MT) was measured with transcranial electric stimulation (TES) administered through the RUL electrodes in the same subjects.

Results: The interindividual anatomical differences resulted in 57% variation in median E-field strength in the brain at fixed stimulus current amplitude. Individualization of the stimulus current by MT reduced the E-field variation in the target motor area by 27%. There was significant correlation between the measured MT and the ratio of simulated electrode current and E-field strength (r(2) = 0.95, p = 0.026). Exploratory analysis revealed significant correlations of this ratio with anatomical parameters including of the superior electrode-to-cortex distance, vertex-to-cortex distance, and brain volume (r(2) > 0.96, p < 0.02). The neural activation threshold was estimated to be 0.45 ±0.07 V/cm for 0.2-ms stimulus pulse width.

Conclusion: These results suggest that our individual-specific NHP E-field models appropriately capture individual anatomical variability relevant to the dosing of TES/ECT. These findings are exploratory due to the small number of subjects.

Significance: This study can contribute insight in NHP studies of ECT and other brain stimulation interventions, help link the results to clinical studies, and ultimately lead to more rational brain stimulation dosing paradigms.

Fig. 1

Overview of the workflow for generating a realistic finite element (FE) model of transcranial electric stimulation (TES) in nonhuman primates (NHPs) for E-field computation and combining it with in vivo motor threshold (MT) data to estimate neural activation threshold. T1-weighted MRI and diffusion tensor MRI data sets of the NHP subjects are acquired. The T1-weighted MRI data are preprocessed using 3D Slicer and in-house image processing pipelines. The T1-weighted MRI images are segmented into 14 tissues using FSL, SPM and ITK-SNAP: example segmentation of the rhesus macaque head shows 3D surface renderings of skin (brown), gray matter (dark gray), and white matter (light gray), and 2D masks of cerebrospinal fluid (CSF, blue), gray matter (red), and white matter (green). The color-coded fractional anisotropy (FA) map and diffusion tensor ellipsoids (enlarged view of the region framed in red) represent the principal orientations (largest eigenvectors) of the tensors (red: left–right, green: anterior–posterior, and blue: superior–inferior). Diffusion tensor data are processed and registered to structural MRI data using FSL. White matter anisotropic conductivity tensors are estimated within MATLAB. Right unilateral (RUL) TES electrodes are incorporated into the head model. The complete 3D TES models are discretized into FE meshes, and the FE models are completed by assigning the tissue electrical conductivities. The E-field distribution is computed using the FE method with ANSYS. Motor threshold is titrated in vivo by the current amplitude of single stimulus pulses. Neural activation threshold is estimated by extracting the simulated E-field strength in the target motor area at the empirical motor threshold current. The E-field strength induced in the brain by the RUL TES electrode configuration is computed at the empirical motor threshold current.

Fig. 2

Individual head models of the four NHP subjects (MA, CH, DY, and RZ, top to bottom rows, respectively) with right unilateral (RUL) TES/ECT electrode configuration. The various conductivity compartments are labeled including (a) RUL stimulation electrodes and tissue segmentation masks including (b) skin, (c) muscle, (d) vertebrae, (e) skull compacta, (f) sclera, (g) gray matter, (h) lens, (i) eyeball, (j) optic nerve, (k) spinal cord, and (l) white matter.

Fig. 3

Simulated E-field strength (magnitude) in the brain induced by the TES/ECT RUL electrode configuration at 800 mA current for the four NHP subjects. The E-field strength (y-axis) is shown on a logarithmic scale to normalize the skewed E-field distribution. Boxes indicate the interquartile range (25th to 75th percentile) with the median marked by the horizontal line within the box, and whiskers delimit the 1st and 99th percentiles of the distribution.

Fig. 4

(a) Measured individual amplitude-titrated RUL TES motor threshold (MT) for 0.2 ms pulse width for the four NHP subjects. (*) The MT for subject CH was different from all other subjects and the MTs for subjects DY and MA differed from each other (p < 0.05). (b) Corresponding estimated E-field neural activation threshold in the motor cortex representation of FDI, computed from the data in (a) and the individual E-field models. The neural activation threshold estimates did not differ significantly among subjects. Bars show mean values and error bars show standard deviation associated with the 3 MT measurements for each subject.

Fig. 5

Simulated E-field distribution at current strength corresponding to the measured individual MT for the four NHP subjects (MA, CH, DY, and RZ, top to bottom rows, respectively). Shown are E-field maps on the cortical surface (CSF–gray matter interface; first column), white matter surface (gray matter–white matter interface; second column), representative coronal slice (third column), and transaxial slices (fourth to six columns; 1.5 mm inter-slice distance). The structural MRI images of the extracerebral brain tissues are shown in gray around the slices as a reference for the anatomical results in Fig. 7. Region-of-interest outlines in white show the FDI representation in motor cortex. Individual average MT is shown on the left below each row. R: right

Fig. 6

Correlation between the average measured MT and the I_electrode/E_FDI ratio computed from the individual FEM simulations of RUL TES/ECT. Pearson’s correlation r² and p values are given in the correlation plot.

Fig. 7

(a) Maps of the distance from the skin surface to the cortex surface plotted over the head surface for the four NHP subjects, measured from the MRI data. Correlation between the simulated I_electrode/E_FDI ratio and the measured (b, c) electrode-to-cortex distance under superior or frontotemporal electrodes, (d) vertex-to-cortex distance, and (e) individual brain volume. Pearson’s correlation r² and p values are given in each correlation plot.