The global improvements in brain blood flow after 1 HBOT in our subjects were associated with improved function after 40 HBOTs, thus supporting the Neubauer effect’s prediction of neurological improvement. SPM analysis demonstrated considerable overlap of the areas with improved blood flow after 1 HBOT with those after 40 HBOTs, indicating that the areas identified on SPECT by the Neubauer effect are likely those responsible for neurological improvement after 40 HBOTs. We have demonstrated the Neubauer effect in severe chronic TBI patients (Harch and Neubauer, 1999, 2004a, 2009b, 2009c; Harch et al., 1994,1996a; Neubauer et al., 1994), along with a pattern shift on SPECT after the first HBOT. The pattern shift consists of normalization (a relative decrease in high and increase in low blood flow; Harch and Neubauer, 1999,2004b; Harch, et al., 1996a) that is captured by a reduction in SD and CV in this study. The first HBOT would not be expected to improve function, however, likely due to the limited impact of a single HBOT on blast-induced degenerated white matter (Bauman et al., 2009).

The increased blood flow on SPECT, variance in MCP change, and improved neurological function seen after 40 HBOT sessions suggests a set of mechanisms different from those that occur after 1 HBOT session. We propose that these mechanisms are the typical trophic mechanisms of HBOT in chronic non-central nervous system wounds (Gesell, 2009). Repetitive HBOT stimulates angiogenesis in chronic non-CNS wounded tissue (Marx et al., 1990), most likely by genomic effects (Godman et al., 2009), and has been shown to increase blood vessel density in injured hippocampus in our chronic rat TBI model, where the progenitor of this HBOT protocol was tested (Harch et al., 2007). HBOT-induced increased hippocampal blood vessel density in this model highly correlated with improved spatial learning and memory. In our subjects SPECT SPM analysis showed significant improvements in blood flow in the hippocampus, while our subjects achieved significant gains in memory. These blood flow and memory improvements seen in our subjects are consistent with a trophic effect of HBOT on chronic brain wounding in the hippocampus, and possible healing/reinnervation of denervated tissue (Bauman et al., 2009).

Other mechanisms may contribute to the HBOT effects seen in our study. A single hyperbaric oxygen re-oxygenation session causes prolonged excitability and neural plasticity of hippocampal neurons after exposure to hypoxia (Garcia et al., 2010), consistent with the Neubauer effect generated in this study. Repetitive HBOT has shown increased neurogenesis and cerebral blood flow in chronic global ischemia (Zhang et al., 2010). Zhang and associates administered repetitive HBOT 30 days after ischemic insult, similar to the 50-day delay in our animal model (Harch et al., 2007). Neurogenesis has been shown to occur in association with angiogenesis (Palmer et al., 2000). As mentioned above, angiogenesis is a known trophic mechanism of HBOT, and may be responsible for the increased blood vessel density seen in our animal model (Harch et al., 2007). HBOT has also been shown to cause the release of bone marrow stem cells into the peripheral circulation (Thom et al., 2006). Peripheral stem cells are known to cross the blood–brain barrier (Mezey et al., 2003).

The limitations of the present study were a lack of confirmation of post-injury brain MRI results in some subjects,

unblinded investigators (except for the SPECT brain imaging SPM analysis), and lack of a control group. The lack of confirmation of brain MRI findings in a few subjects could confound study results only by inadvertent inclusion of nonclinically-apparent neurological disease that was manifest on MRI alone. We believe this is a very remote possibility; these young men were highly fit pre-military, underwent regular fitness evaluations while in the military, and had no premorbid disqualifying conditions. All symptomatology commenced with the incident blast and was present continuously since the blast. Routine late MRI evaluations in mild to moderate TBI are usually negative, consistent with the majority of the scans in our subjects. We presume the few missing data points would similarly be normal or non-contributory.

Investigator bias and placebo effects possibly contributed to the magnitude of some of the effects we measured, but are unlikely to account for the majority of the effects or the consistency and magnitude of the effects seen across all domains, particularly SPECT. Investigator bias could be present in the P.I.’s symptom and physical exam recording, and in S.R.A.’s neuropsychological testing, but it does not explain the significant SPECT findings for which separate independent analyses, one of which was blinded, were performed by E.F.F. in North Dakota and D.A. and D.V.T. in California. None of the SPECT co-investigators interacted with the subjects, and they performed their analyses months after the subjects had completed their final imaging. Importantly, the blinded SPECT analyst, D.V.T., produced the most significant statistical results.

Placebo effects cannot be entirely ruled out; however, there are multiple arguments against this notion. Treatment effect size in two meta-analyses of randomized placebo-controlled trials versus observational studies performed on the same treatments has been shown to be very similar (Benson and Hartz, 2000; Concato et al., 2000). This suggests that placebo effects are overestimated in observational studies such as ours. Placebo effects on many of the cognitive measures in our study have been reported to be smaller than the changes we found with HBOT for FSIQ and WMS Visual Immediate and Delayed Memory (Doraiswamy et al., 2007), for Stroop Reaction Time (Calabrese et al., 2008), and for Stroop Color/Word raw score ( Jorge et al., 2010). The placebo effects reported on SPECT in psychiatric disease, in healthy individuals, and in neurological disease have shown focal changes in regional cerebral blood flow (Beauregard, 2009), most commonly in the inferior frontal gyrus, striatum, and rostral anterior cingulate cortex ( Jarcho et al., 2009). The global diffuse changes we measured have not been reported. In addition, it is highly improbable that a placebo effect could account for the multiplicity of differential changes on SPECT seen after 1 and 40 HBOTs using two different forms of mathematical/statistical analyses. Lastly, the parallel improvements in memory scores and hippocampal blood flow are inconsistent with a placebo effect.

Test/retest practice effects could explain some of the cognitive improvements; however, practice effects do not fully explain our measured increases for seven reasons. (1) Practice effects on the WAIS-III FSIQ over a mean 34.6-day retest interval have been shown to be 2.0–3.2 points across all age groups, 6 points in the 16- to 29-year-old group, and decrease with age; our subjects averaged 30 years old (Tulsky and Zhu, 1997). They have also been shown to increase 6 points over 3-or 6-month retest times (Basso et al., 2002). Six points is 41% of the measured FSIQ increase on the WAIS-IV in our subjects. (2) The bulk of practice effects occur on the first retest (Bartels et al., 2010; Falleti et al., 2006), and our subjects had been cognitively tested at least once before our pre-HBOT testing session. Second and third retest (third and fourth tests) effects should have been smaller than 6 points. (3) Working memory has been shown to be among the most resistant to practice/retest effects (Bartels et al., 2010; Basso et al., 2002). Our subjects averaged a 9.9-point statistically significant improvement. (4) Practice effects are usually studied in normal individuals with intact memory function. Intact memory is a prerequisite for learning/practice effects. In individuals with impaired memory function, such as our subjects, practice effects may be less (Basso et al., 2002). (5) We used the alternate form WASI for the post-treatment IQ test in order to minimize practice effects. (6) A Stroop Color/Word score increase in a controlled HBOT study of chronic brain injury produced results similar to ours (Golden et al., 2006). (7) Stroop Color/Word test/retest effects across 1- and 2-week intervals are 3.83 points (Franzen et al., 1987), and our increase was 11.0 points.

Our results were achieved with half (40 HBOTs) of our normal protocol (80 HBOTs) on an accelerated twice/day schedule due to time and fiscal constraints. Through clinical experience, clinical research, and an animal pilot study that compared sham HBOT, 40, and 80 HBOTs (Harch et al., 1996b), we found greater cognitive and blood flow improvements (in an animal model; Harch et al., 2007), and clinical and blood flow improvements (in human cases) with 80 HBOTs, but the cases were primarily chronic moderate to severe TBI (vide supra). Neubauer and Golden (Golden et al., 2002) reported progressively greater blood flow in a case series of chronic severe brain-injured patients receiving 70 low pressure HBOTs. Recently, Wright and colleagues (2010) reported the effectiveness of our HBOT 1.5 ATA protocol in two airmenwith blast-induced PCS, using 40 and 80 HBOTs (for persistent symptoms after 40 HBOTs). Our subjects finished HBOT with partial improvement in their symptoms. It is likely that additional HBOT sessions would be beneficial.

In conclusion, application of a lower-pressure protocol of 40 HBOTs at 1.5 ATA to a 16-subject cohort of military subjects with blast-induced chronic PCS and PTSD was found to be safe. One fourth of the subjects experienced transient clinical deterioration halfway through the protocol and one subject did not finish. Simultaneously, as a group the 15 subjects experienced notable improvements in symptoms, abnormal physical exam findings, cognitive testing, PCS and PTSD symptom questionnaires, quality-of-life questionnaires, depression and anxiety indices, and SPECT brain blood flow imaging that are inconsistent with the natural history of PCS 2.8 years post-injury. The symptomatic improvements were present at 6-month phone follow-up in 92% of subjects who reported improvement after 40 HBOTs. More objective psychometric testing and SPECT imaging were not performed to confirm the durability of the HBOT treatment effect. Sixty-four percent of the patients on psychoactive and narcotic prescription medications were able to decrease or eliminate use of these medications. These data are preliminary and need confirmation with larger numbers of subjects or with a stronger design such as a randomized or Bayesian study.

Acknowledgments

The authors thank The Marine Corps Law Enforcement Foundation, The Semper Fi Fund, The Coalition to Salute Americas Heroes, the Harch Hyperbaric Research Fund of the Baromedical Research Institute of New Orleans, Mr. Caleb Gates, New Orleans Natural Resource Group, Rubie and Bryan Bell, Martin and Margaret Hoffmann, John and Virginia Weinmann, Dr. Warren Thomas, Joan C. White, Health Freedom Foundation, Soldiers Angels, Operation Homefront Louisiana, The Audubon Society, Mr. Theodore Solomon, New Orleans Steamboat Company, the National WWII Museum, and Westwego Swamp Boat Tours for their generous donations. We thank Mr. Martin Hoffmann, ex-Secretary of the Army (President Gerald Ford) for his indefatigable fundraising efforts, Sean Bal and Ray Crowell, our hyperbaric technicians for their expert and safe delivery of hyperbaric oxygen therapy, Wanda Phillips for review of all of the study records, and Amy Trosclair of the BRI for overseeing the handling and disbursement of funds.

Author Disclosure Statement

Dr. Harch owns a small consulting company called Harch Hyperbarics, Inc., which has no contracts. For Dr. Andrews no competing financial interests exist. Juliette Lucarini, R.N. is a tenant in common ownership of Harch Hyperbarics, Inc. For Claire Aubrey, Dr. Fogarty, and Dr. Staab no competing financial interests exist. Dr. Pezzullo is an independent statistical consultant for whom no competing financial interests exist. For Dr. Amen and Derek Taylor no competing financial interests exist. Dr. Van Meter has a hyperbaric equipment leasing company and contracts with hospitals to provide hyperbaric medicine physician staffing.

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Address correspondence to:

Paul G. Harch, M.D.

Hyperbaric Medicine Department

Department of Medicine

Section of Emergency and Hyperbaric Medicine

Louisiana State University Health Sciences Center

1542 Tulane Avenue, Room 452, Box T4M2

New Orleans, LA 70112

E-mail: [email protected]

Appendix

Standardized questionnaire:

Energy level on 1–10 scale (10 was pre-LOC energy level, 0 is inability to get out of bed). Weight change since injury. Mood swings. Irritability/short temper. Mood, 1–10 scale (10 is happiest in life, 0 is not wanting to live). Cranial and cranial nerve symptoms: headache, dizziness, visual symptoms, loss of hearing, tinnitus, vertigo, change in smell/taste, trouble talking, enunciating, swallowing, or chewing. Sensory symptoms: numbness, tingling. Motor: focal or generalized weakness. Incoordination: fine motor (hands/fingers), gross motor (tripping, stumbling, imbalance). Cognitive: trouble thinking/grasping ideas, organizing thoughts, decreased speed of thinking, confusion, problems following directions/instructions, difficulty expressing thoughts/word-finding, forgetfulness, misplacing/losing things, problems remembering old information or new information, losing one’s place in thought or conversation or while driving, going blank, staring episodes, feeling suddenly lost or disoriented, concentration/attention problems, difficulty writing, family or friends commenting on change in personality or behavior. Joint pain or swelling. Incontinence of bowel or bladder.

Neurological exam:

Cranial nerves: II–XII. Deep tendon reflexes upper and lower extremities. Motor: tone, mass, tremor, deep knee bend, strength, tiptoe, and heel walking. Sensory: pinprick and touch in the four extremities. Gait: normal, tandem (slow and fast). Pathological reflexes: glabellar, snout, palmomental, grasp, suck, root, Hoffman, Babinski, clonus. Cerebellar: Romberg, finger tapping speed/rhythm, elbow flexion check response, finger-to-nose testing, heel-to-shin gliding, rapid alternating hand movementspalm/dorsal hand thigh slapping.

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1Hyperbaric Medicine Department, Department of Medicine, Section of Emergency and Hyperbaric Medicine,

2Department of Medicine and Psychiatry, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana.

3Department of Radiology, University of North Dakota School of Medicine and Health Sciences, Bismarck, North Dakota.

4University of California, Irvine, School of Medicine, Amen Clinics, Inc., Newport Beach, California.

5Department of Medicine, Georgetown University Medical Center, Washington, D.C.

6Administrative Office, New Orleans, Louisiana.

Key words: hyperbaric oxygen therapy; post-concussion syndrome; post-traumatic stress disorder; single photon emission computed tomography; chronic traumatic brain injury; TBI; PCS; PTSD