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Dear Editor, The recent study by Wolf and associates has affirmed the effectiveness of hyperbaric (oxygen) therapy in the treatment of patients with mild traumatic brain injury (mTBI)/post-concussion syndrome (PCS) and post-traumatic stress disorder (PTSD). This affirmation emerges from analysis of the study data, rather than from the study’s stated conclusions. Mischaracterized as a shamcontrolled (placebo implied) design, the study errs in concluding that ‘‘HBO2 at 2.4 ATA pressure had no effect on post-concussive symptoms after mild TBI.’’ A reconsideration of the science of hyperbaric therapy reveals that the study by Wolf and colleagues is neither a sham nor placebo-controlled study. Rather, it is a Phase II study of two composite doses of hyperbaric therapy that demonstrated significant improvements in PCS and PTSD symptoms at the 2.4 atmospheres absolute (ATA) pure oxygen dose as well as the low-pressure 1.3 ATA air/oxygen dose. Hyperbaric (oxygen) therapy (HBOT) is a combination product of increased pressure and increased pressure of oxygen above ambient atmospheric pressure, according to scientific principles and current Food and Drug Administration understanding. Although traditionally misdefined as a treatment for diseases based on the increased oxygen component alone ( > 1.4 ATA oxygen), it is a treatment with hyperbaric pressure and hyperoxia for disease processes whose primary targets are oxygen and pressure sensitive genes. Evidence for this dual component nature of hyperbaric therapy is found in the 351-year history of hyperbaric air therapy and the recent 60-year history of animal, human tissue, and human experiments that have documented biological effects of pressure, especially in the micropressure range of the Wolf and coworkers ‘‘sham’’ control group and the control groups of the Department of Defense (DoD) HBOT TBI studies. Examples of this literature are listed in Tables 1 and 2. Pressures from 1.21–1.26 ATA delivered to human and 1.0015–1.015 ATA to animal endothelial cells, and 1.10 and 1.20 ATA to human platelets for 15 min or longer have caused the elaboration or suppression of vasoactive substances, and the elaboration of growth factors, inflammatory mediators, oxidation products, and cell proliferation. This literature and biological effects from a 1-min exposure to 1.09 ATA or 3 min at 1.04 ATA inform the symptomatic improvements noted in the Wolf and associates ‘‘sham’’ group, as do benefits of hyperbaric air on spinal function and PTSD in spinal cord injured veterans during a SCUBA diving training course. To meet the definition of a true sham, any controlled experiment to test HBOT must omit in its control groups the active ingredients of increased pressure and hyperoxia. The Wolf and colleagues ‘‘sham’’ control group does neither; rather, it includes both. The ‘‘sham’’ control group is exposed to 1.3/1.2 ATA of air, which is a 20–30% increase in pressure and 28–43% increase in plasma oxygen over sea level plasma oxygen and a slightly greater increase over San Antonio (hyperbaric treatment site) atmospheric pressure. Because pressure and hyperoxia are noninert—i.e., are biologically active—the Wolf and coworkers ‘‘sham’’ control group cannot test for placebo effects; placebo/ placebo response is defined as ‘‘The effect that an inactive or inert substance has on a clinical condition.’’ Wolf and associates allude to possible bioactivity of the control group, but the lack of discussion indicates a lack of appreciation that the presence of hyperoxia and pressure negate Wolf and colleagues characterization as a ‘‘sham’’ control group. Restating the design of the Wolf and coworkers study, it is a Phase II comparative dosing study of two composite doses of hyperbaric therapy (four actual doses), compressed air (low dose increased pressure and increased oxygen), and compressed oxygen (high dose pressure and high dose oxygen). Both doses were efficacious in the treatment of mTBI PCS and PTSD. The PTSD data demonstrated 18% and 22% reductions in the PCL-M (interpolated from the Figure 1 graph in Wolf and colleagues) in the HBOT and ‘‘sham’’ groups, respectively, after 30 2 h treatments. These reductions compared favorably with five other therapies/six studies for PTSD that used the PCL-M (6–45% reductions). The PCS ImPACT data were similarly significantly improved in both groups, but it is the disparity in component and pattern change on the ImPACT results for the two groups that underscore the dual dose design of the study and efficacy of these two doses: 10 IMPACT scores significantly improved in the low dose group compared with 2 in the high dose group. For all 22 items of the ImPACT, 20 improved, 1 was unchanged, and 1 was worse in the

Hyperbaric Oxygen Therapy for Post-Concussion Syndrome: Contradictory Conclusions from a Study Mischaracterized as Sham-Controlled