Effect of Transcranial Low-Level Light Therapy vs Sham Therapy Among Patients With Moderate Traumatic Brain Injury: A Randomized Clinical Trial

Abstract

Importance: Preclinical studies have shown that transcranial near-infrared low-level light therapy (LLLT) administered after traumatic brain injury (TBI) confers a neuroprotective response.

Objectives: To assess the feasibility and safety of LLLT administered acutely after a moderate TBI and the neuroreactivity to LLLT through quantitative magnetic resonance imaging metrics and neurocognitive assessment.

Design, setting, and participants: A randomized, single-center, prospective, double-blind, placebo-controlled parallel-group trial was conducted from November 27, 2015, through July 11, 2019. Participants included 68 men and women with acute, nonpenetrating, moderate TBI who were randomized to LLLT or sham treatment. Analysis of the response-evaluable population was conducted.

Interventions: Transcranial LLLT was administered using a custom-built helmet starting within 72 hours after the trauma. Magnetic resonance imaging was performed in the acute (within 72 hours), early subacute (2-3 weeks), and late subacute (approximately 3 months) stages of recovery. Clinical assessments were performed concomitantly and at 6 months via the Rivermead Post-Concussion Questionnaire (RPQ), a 16-item questionnaire with each item assessed on a 5-point scale ranging from 0 (no problem) to 4 (severe problem).

Main outcomes and measures: The number of participants to successfully and safely complete LLLT without any adverse events within the first 7 days after the therapy was the primary outcome measure. Secondary outcomes were the differential effect of LLLT on MR brain diffusion parameters and RPQ scores compared with the sham group.

Results: Of the 68 patients who were randomized (33 to LLLT and 35 to sham therapy), 28 completed at least 1 LLLT session. No adverse events referable to LLLT were reported. Forty-three patients (22 men [51.2%]; mean [SD] age, 50.49 [17.44] years]) completed the study with at least 1 magnetic resonance imaging scan: 19 individuals in the LLLT group and 24 in the sham treatment group. Radial diffusivity (RD), mean diffusivity (MD), and fractional anisotropy (FA) showed significant time and treatment interaction at 3-month time point (RD: 0.013; 95% CI, 0.006 to 0.019; P < .001; MD: 0.008; 95% CI, 0.001 to 0.015; P = .03; FA: -0.018; 95% CI, -0.026 to -0.010; P < .001).The LLLT group had lower RPQ scores, but this effect did not reach statistical significance (time effect P = .39, treatment effect P = .61, and time × treatment effect P = .91).

Conclusions and relevance: In this randomized clinical trial, LLLT was feasible in all patients and did not exhibit any adverse events. Light therapy altered multiple diffusion tensor parameters in a statistically significant manner in the late subacute stage. This study provides the first human evidence to date that light therapy engages neural substrates that play a role in the pathophysiologic factors of moderate TBI and also suggests diffusion imaging as the biomarker of therapeutic response.

Trial registration: ClinicalTrials.gov Identifier: NCT02233413.

Figure 1.. Patient Flow Diagram

MRI indicates magnetic resonance imaging.

Figure 2.. Evolution of Clinical Symptoms of Traumatic Brain Injury (TBI) in the Low-Level Light Therapy and Sham Groups

Scores on the Rivermead Post-Concussion Symptoms Questionnaire, a 16-item self-assessment questionnaire. Each item in the questionnaire is assessed on a 5-point scale ranging from 0 (no problem) to 4 (severe problem). Bars show the standard error of the mean. A, Scores from RPQ-3 assessment, including early, objective, and physical symptoms of TBI. Time: P < .001, treatment: P = .40, and time × treatment: P = .97. B, Scores from RPQ-13 assessment, including later, more cognitive and behavioral symptoms. Time: P = .91, treatment: P = .67, and time × treatment: P = .89. C, Total RPQ scores. Time: P = .39, treatment: P = .61, and time × treatment: P = .91.

Figure 3.. Effect of Light Treatment on Diffusion Parameters

The effect of light treatment on diffusion parameters as predicted by linear mixed effect model. Error bars represent standard error of the mean. A, Axial diffusivity. Time, P = .02; treatment, P = .89; time x treatment, P = .47. B. Mean diffusivity. Time, P = .04; treatment, P = .08; time x treatment, P < .001. C, Radial diffusivity. Time, P = .11; treatment, P = .77, time x treatment, P < .001. D, Fractional anisotropy. Time, P = .02; treatment, P = .58; time x treatment, P < .001.