Safety and tolerability of transcranial direct current stimulation to stroke patients - A phase I current escalation study

Abstract

Background and objective: A prior meta-analysis revealed that higher doses of transcranial direct current stimulation (tDCS) have a better post-stroke upper-extremity motor recovery. While this finding suggests that currents greater than the typically used 2 mA may be more efficacious, the safety and tolerability of higher currents have not been assessed in stroke patients. We aim to assess the safety and tolerability of single session of up to 4 mA in stroke patients.

Methods: We adapted a traditional 3 + 3 study design with a current escalation schedule of 1»2»2.5»3»3.5»4 mA for this tDCS safety study. We administered one 30-min session of bihemispheric montage tDCS and simultaneous customary occupational therapy to patients with first-ever ischemic stroke. We assessed safety with pre-defined stopping rules and investigated tolerability through a questionnaire. Additionally, we monitored body resistance and skin temperature in real-time at the electrode contact site.

Results: Eighteen patients completed the study. The current was escalated to 4 mA without meeting the pre-defined stopping rules or causing any major safety concern. 50% of patients experienced transient skin redness without injury. No rise in temperature (range 26°C-35 °C) was noted and skin barrier function remained intact (i.e. body resistance >1 kΩ).

Conclusion: Our phase I safety study supports that single session of bihemispheric tDCS with current up to 4 mA is safe and tolerable in stroke patients. A phase II study to further test the safety and preliminary efficacy with multi-session tDCS at 4 mA (as compared with lower current and sham stimulation) is a logical next step. ClinicalTrials.gov Identifier: NCT02763826.

Keywords: 3+3 design; Dose escalation; High-dose; Non-invasive brain stimulation; Stroke recovery; Transcranial direct current stimulation.

Figure 1. Established brain lesion threshold from an animal study is more than 50-times higher than typical (≤2 mA) human tDCS setup

tDCS current of 2 mA delivered for 30 minutes using 35 cm² is much smaller than the charge that was reported to incur brain damage (1029 vs 52400 C/m²). Tested safety limit of 4 mA proposed in this study is still about 25× smaller (2057 vs 52400 C/m²). Adapted from [19], note that charge density on azimuth is projected on a logarithmic scale.

Figure 2. 3+3 dose escalation trial design

Subjects were tested at incremental dose/current levels of 1.0, 2.0, 2.5, 3.0, 3.5 and 4.0 mA, making six dose/current levels with minimum three subjects at each dose/current level.

Figure 3. Quantitative analysis of change in Apparent Diffusion Coefficient (ADC) map as a result of tDCS

A, Axial and coronal view of the 5 × 7 cm² mask (yellow outline) to calculate ADC values after excluding scalp, skull and cerebrospinal fluid (CSF). B, Axial view of the subtraction ADC map of the same subject presented in A with the mask overlay. C, Percent change in ADC values of individual subjects at anode (blue) and cathode (green) at each tDCS dose level and also mean ADC change (dots joined by lines). One subject who received 2 mA dose level had mismatched MRI image and therefore could not have accurate percent change ADC calculation and therefore presented with ~10% decrease in ADC as a result.

Figure 4. Real-time monitoring of tDCS delivery confirmed safety

The skin temperature at electrode-skin contact sites remained well below normal body temperature value of 37°C (range 26°C–35°C). Body r esistance was always higher than 2 kΩ suggesting no breach in the skin barrier function.