Incomplete evidence that increasing current intensity of tDCS boosts outcomes

Abstract

Background: Transcranial direct current stimulation (tDCS) is investigated to modulate neuronal function by applying a fixed low-intensity direct current to scalp.

Objectives: We critically discuss evidence for a monotonic response in effect size with increasing current intensity, with a specific focus on a question if increasing applied current enhance the efficacy of tDCS.

Methods: We analyzed tDCS intensity does-response from different perspectives including biophysical modeling, animal modeling, human neurophysiology, neuroimaging and behavioral/clinical measures. Further, we discuss approaches to design dose-response trials.

Results: Physical models predict electric field in the brain increases with applied tDCS intensity. Data from animal studies are lacking since a range of relevant low-intensities is rarely tested. Results from imaging studies are ambiguous while human neurophysiology, including using transcranial magnetic stimulation (TMS) as a probe, suggests a complex state-dependent non-monotonic dose response. The diffusivity of brain current flow produced by conventional tDCS montages complicates this analysis, with relatively few studies on focal High Definition (HD)-tDCS. In behavioral and clinical trials, only a limited range of intensities (1-2 mA), and typically just one intensity, are conventionally tested; moreover, outcomes are subject brain-state dependent. Measurements and models of current flow show that for the same applied current, substantial differences in brain current occur across individuals. Trials are thus subject to inter-individual differences that complicate consideration of population-level dose response.

Conclusion: The presence or absence of simple dose response does not impact how efficacious a given tDCS dose is for a given indication. Understanding dose-response in human applications of tDCS is needed for protocol optimization including individualized dose to reduce outcome variability, which requires intelligent design of dose-response studies.

Keywords: Dose-control; Dose-response; Neuromodulation; Transcranial direct current stimulation (tDCS).

Fig. 1.

An aggregate linear tDCS intensity dose response requires linear input-output function in each scale from a single neuron to local neuronal circuits and plasticity, to large scale interconnected neuronal networks and ultimately behavior and task performance. Induced electric field (or current intensity) in the brain increases linearly with applied stimulation current. In well-controlled, in-vitro experiments, increased membrane polarization can be reasonably assumed with increasing tDCS intensity but in an active brain, nonlinear and complex behavior is more likely. Different experimental, modeling and imaging techniques assist to map tDCS modulation in specific scales.

Fig. 2.

Cortical electric field intensity and pattern across two different subjects (Head #1, Head #2) and standard averaged head (Head #3) for 1 mA stimulation using different electrode montages. A: anode (red) over left M1 and cathode (blue) over contralateral-supraorbital across different heads (A.1, A.2, A.3). B: bilateral DLPFC, anode (red) over left DLPFC (F3, EEG standard system) and cathode (blue) over right DLPFC (F4, EEG standard system) across different heads (B.1, B.2, B.3). Conventional pad electrodes deliver current to multiple brain regions that varies across subjects. For HD-tDCS configuration, C: anode (red) over M1 and cathodes (blue) with 6 mm center to center distance from anode for three different heads (C.1, C.2, C.3). ROI, region of interest. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3.

Experimental design of dose-response studies in animal and man. 6 experimental paradigms are illustrated, 2 in animal and 4 in human trials. Approaches where electric field is controlled (left column) are contrasted with approaches where applied current is fixed (right column). In human trial panels, the use of anatomical MRI scans is illustrated by a MRI cartoon. The use of a tDCS or HD-tDCS montage is illustrated on two semi-transparent head. Predicted electric field are shown in false color on the cortex. In each case, one or more outcome measures would be correlated against electric field in the ROI or the applied current, with the question-mark indicating a monotonic relationship is not necessarily established. The nominal ROI may be assumed to be “under” one electrode (red circle) with other brain region considered (yellow and black circles). In each panel, a simplified representation of the electric field distribution across a population (three stick figure cartoon) includes three brain regions (the nominal ROI in red, and other brain regions in yellow, black). These regions may be interconnected such that the outcome measure can reflect aggregate network stimulation. (A.1) In vitro animal brain slice models are stimulated with a uniform electric field. The electric field can be increased and an outcome measure recorded. Few in vitro studies applied several increments of electric magnitude in the tDCS range (<1 V/m). (A.2) In vivo animal models apply a fixed current with an epi-cranial electrode which results is animal-specific electric field in the ROI (red) and varied electric fields in other brain regions (Yellow, Black). Increasing the applied current increases all the electric field in each brain region proportionally. Electric field in animal models will be dramatically above the human case when comparable currents are applied. An outcome measures is recorded at varied applied current levels. (B.1) Using conventional electrode pads, controlled electric field intensity can be applied to a ROI in human trials by varying the applied current in each individual to generate a fixed electric field at the ROI. They require individual current flow modeling. The electric fields in other brain regions are not controlled and so vary across individuals and may be higher than in the ROI. An outcome measures is recorded at varied controlled ROI electric fields. (B.2) Using conventional electrode pads, a fixed current is applied across subjects for each dose, which results in variable electric field at the ROI as well as at other brain regions. For each subject, increasing the applied current increases all the electric field in each brain region proportionally. The electric field may be maximal outside the ROI. An outcome measures is recorded at varied applied current. [shaded inset] Post-hoc individual model may be used to reanalyze data based on predicted electric field in the ROI. This may result in some subjects in the lower-current group having a higher electric field at the ROI than some subjects in the low current group. (C.1) Using the high-definition 4 × 1 montage, controlled intensity electric field can be applied to a ROI in human trials by varying the applied current in each individual to generate a fixed electric field at the ROI. The require individual current flow modeling based on MRI. Across individuals, the electric field is predicted to be focal and maximal at the ROI across stimulation intensities. An outcome measures is recorded at varied controlled ROI electric fields. (B.2) Using the high-definition 4 × 1 montage, fixed currents are applied across, which results in variable electric field at the ROI at each current, however, the maximal electric field remains in the ROI across individuals. For each subject, increasing the applied current increases all the electric field in each brain region proportionally, but the electric field remains minimal outside the ROI. An outcome measures is recorded at varied applied current. [shaded inset] Post-hoc individual model may be used to reanalyze data based on predicted electric field in the ROI. This may result in some subjects in the lower-current group having a higher electric field at the ROI than some subjects in the low current group. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)