Alternating Current Stimulation for Vision Restoration after Optic Nerve Damage: A Randomized Clinical Trial

Abstract

Background: Vision loss after optic neuropathy is considered irreversible. Here, repetitive transorbital alternating current stimulation (rtACS) was applied in partially blind patients with the goal of activating their residual vision.

Methods: We conducted a multicenter, prospective, randomized, double-blind, sham-controlled trial in an ambulatory setting with daily application of rtACS (n = 45) or sham-stimulation (n = 37) for 50 min for a duration of 10 week days. A volunteer sample of patients with optic nerve damage (mean age 59.1 yrs) was recruited. The primary outcome measure for efficacy was super-threshold visual fields with 48 hrs after the last treatment day and at 2-months follow-up. Secondary outcome measures were near-threshold visual fields, reaction time, visual acuity, and resting-state EEGs to assess changes in brain physiology.

Results: The rtACS-treated group had a mean improvement in visual field of 24.0% which was significantly greater than after sham-stimulation (2.5%). This improvement persisted for at least 2 months in terms of both within- and between-group comparisons. Secondary analyses revealed improvements of near-threshold visual fields in the central 5° and increased thresholds in static perimetry after rtACS and improved reaction times, but visual acuity did not change compared to shams. Visual field improvement induced by rtACS was associated with EEG power-spectra and coherence alterations in visual cortical networks which are interpreted as signs of neuromodulation. Current flow simulation indicates current in the frontal cortex, eye, and optic nerve and in the subcortical but not in the cortical regions.

Conclusion: rtACS treatment is a safe and effective means to partially restore vision after optic nerve damage probably by modulating brain plasticity. This class 1 evidence suggests that visual fields can be improved in a clinically meaningful way.

Trial registration: ClinicalTrials.gov NCT01280877.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Consort flow chart and study design.

(A) Patient flow for cases included in the primary outcome measure analysis. Of 98 eligible patients, 45 were treated with rtACS and 37 with sham-stimulation. Five subjects left the study between initial screening and BASELINE for different reasons and another five subjects were excluded due to violation of an inclusion criterion (unacceptable fluctuations between initial screening and BASELINE). During the treatment phase three subjects dropped out because of medical conditions that were unrelated to study participation. Three treated cases of legally blind subjects were excluded from subsequent analyses due to violation of inclusion criterion (no residual vision). (B) Study design with diagnostic and treatment visits. Randomization was done after BASELINE assessment. Stability of VF defects was ascertained by comparing VFs at BASELINE with those obtained during the screening visit 2 weeks earlier. Upon completion of the 10-day treatment, all initial diagnostic tests were repeated (POST). The FOLLOW-UP diagnostic assessment was conducted after a therapy-free interval of at least 2 months.

Fig 2. Perimetry measures and EEG.

(A) Primary and secondary analyses of VF outcome between- and within-groups after rtACS and sham-stimulation bar charts of primary (first upper graph) and secondary parameters of VF diagnostics measured using HRP and standard-automated static and kinetic perimetry. Results are given as medians and 95%-CI. Between-group comparisons were performed according to a pre-defined hypothesis using a one-sided U-test. Within-group BASELINE vs. POST and BASELINE vs. FOLLOW-UP comparisons were calculated separately for each treatment arm using Wilcoxon matched-pairs signed rank tests. The respective p-values are reported with p<0.05 considered as significant. (B) Individual change in HRP VF charts at BASELINE and POST in the two best responding patients of both groups. By superimposing HRP computer campimetric VF charts of three repeated measurements, VF areas were categorized as intact (perfect stimulus detection at a given location, white spots), partially damaged/relative defect (inconsistent stimulus detection, grey spots), and absolutely impaired areas (no stimulus detected, black spots). Detection increases and decreases after intervention are shown in blue and red, respectively. The percentage improvement of the detection accuracy was comparable between the whole HRP VF 16x21.5° and the central 5° VF. (C) Power spectra before and after the first stimulation session. Left sub-figure: One session of tACS increased power of theta (Z = 3.583, p<0.001), alpha (t = 4.571, p<0.001) and beta bands (Z = 3.142, p = 0.002) recorded from electrode positions above the visual cortex. Middle sub-figure: After sham stimulation a significant power increase was observed for only the theta band (Z = 3.147, p = 0.002). Right sub-figure: Scatter plot showing the relation between change in alpha band coherence at the occipital area of interest and change in detection accuracy in total visual field (primary outcome measure).

Fig 3

Visualization of simulated electrical fields during rtACS: current density maxima on eye/optical nerve (A), brain tissue surface (B) and in the volume (C). Although four electrodes were used for treatment, they were used only one at a time. Therefore, the current flow simulation was done with only one electrode, representing all other electrodes. (A) Current density maxima of about 0.0044 A/m2 can be observed on the upper part of the outer eye surface that is closest to the stimulating electrode. Furthermore, the optical nerve of the stimulated eye also receives parts of the stimulating current density magnitude as currents enter the inner skull. (B) Local current density maxima can be found at frontal brain regions spatially located close to the stimulating anodal electrode. (C) Another area of locally increased current density can be found at the brain stem and lower cerebellum.