Abstract: Traumatic brain injury (TBI) remains a significant public health concern, with mild cases accounting for the majority of incidents. However, a substantial percentage of individuals with mild TBI continue to experience chronic neurocognitive impairments. This study aimed to assess the efficacy of hyperbaric oxygen therapy (HBOT) in enhancing brain function and improving the quality of life in patients with mild TBI and prolonged post-concussion syndrome (PCS).

Methods and Findings: The trial involved 56 patients with mild TBI, 1–5 years post-injury, experiencing prolonged PCS. Employing a prospective, randomized, crossover-controlled trial design, participants were randomly assigned to either the treated or crossover group. The treated group underwent cognitive and quality-of-life assessments at baseline and after 40 HBOT sessions. The crossover group was assessed at baseline, after a 2-month control period without treatment, and after subsequent 2-month HBOT sessions. The HBOT protocol consisted of 40 sessions (5 days/week), each lasting 60 minutes, with 100% oxygen at 1.5 ATA. Cognitive function was evaluated using “mindstreams,” quality of life was assessed via EQ-5D, and SPECT imaging measured changes in brain activity. Significant improvements in cognitive function and quality of life were observed in both groups following HBOT, with no significant changes during the control period. SPECT imaging revealed heightened brain activity, aligning with the cognitive improvements.

Conclusions: This study suggests that HBOT holds promise in inducing neuroplasticity, facilitating the restoration of chronically impaired brain functions, and enhancing the quality of life in individuals with mild TBI and prolonged PCS during the late chronic stage.